Bispecific antibody against cd3 and cd20 in combination therapy for treating diffuse large b-cell lymphoma

ABSTRACT

Provided are methods of clinical treatment of diffuse large B-cell lymphoma (DLBCL) (e.g., previously untreated, high-risk DLBCL) in human subjects using a bispecific antibody which binds to CD3 and CD20 in combination with standard of care regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

FIELD

The present invention relates to bispecific antibodies targeting bothCD3 and CD20 and the use of such antibodies in combination with astandard of care R-CHOP (rituximab, cyclophosphamide, doxorubicin,vincristine, prednisolone) regimen for the treatment of diffuse largeB-cell lymphoma (DLBCL), for example, previously untreated high-riskDLBCL. Advantageous treatment regimens are also provided.

BACKGROUND

DLBCL is the most common non-Hodgkin lymphoma (NHL), and the standardfirst-line therapy is R-CHOP. The cure rate of this combination for theoverall population of newly-diagnosed DLBCL is between 60% and 70% (Sehnet al., Blood 2007; 109:1867-61). Attempts to improve upon outcomes offirst-line therapy, including intensification of dose and addition ofother agents to intensify the regimen, have failed to provide sufficientevidence to alter standard of care.

Risk factors impacting rates of CR to first-line treatment, diseaserelapse, and OS are included in the International Prognostic Index (IPI)or Revised-IPI (R-IPI): age >60 years, ECOG >1 or KPS <60, LDH >ULN;extranodal disease >1 (2 or more), and disease Stage 3 or 4 (Project etal., N Engl J Med 1993; 329:987-994; Sehn et al., supra). While patientsin the good risk group (1-2 IPI factors) have a 4-year PFS of 80%following standard first-line R-CHOP, the 45% of patients in the poorrisk (high risk) group (3-5 IPI factors) only achieve a 4-year PFS andOS of 55% (Sehn et al., supra).

Given the limited efficacy and long-term response of poor risk subjectsto currently available treatments, novel and effective treatments areneeded.

SUMMARY

Provided herein are methods of treating human subjects who have DLBCL,for example, previously untreated DLBCL (e.g., DLBCL with high-riskfeatures (e.g., IPI or R-IPI ≥3)), by administering a bispecificantibody which binds to CD3 and CD20 in combination with a standard ofcare R-CHOP regimen, in particular, advantageous clinical treatmentregimens.

In one aspect, provided herein is a method of treating diffuse largeB-cell lymphoma (DLBCL) in a human subject, the method comprisingadministering to the subject the combination of epcoritamab with R-CHOP,e.g., the method comprising administering to the subject an effectiveamount of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d)vincristine, (e) prednisone, and (f) epcoritamab.

In one aspect, provided herein is a method of treating diffuse largeB-cell lymphoma (DLBCL) in a human subject, the method comprisingadministering to the subject a bispecific antibody and an effectiveamount of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d)vincristine, (e) prednisone, wherein the bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a        variable heavy chain (VH) region and a variable light chain (VL)        region, wherein the VH region comprises the CDR1, CDR2 and CDR3        sequences that are in the VH region sequence of SEQ ID NO: 6,        and the VL region comprises the CDR1, CDR2 and CDR3 sequences        that are in the VL region sequence of SEQ ID NO: 7; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region and a        VL region, wherein the VH region comprises the CDR1, CDR2 and        CDR3 sequences that are in the VH region sequence of SEQ ID NO:        13, and the VL region comprises the CDR1, CDR2 and CDR3        sequences that are in the VL region sequence of SEQ ID NO: 14;    -   wherein the bispecific antibody is administered at a dose of 24        mg or 48 mg, and wherein rituximab, cyclophosphamide,        doxorubicin, vincristine, prednisone, and the bispecific        antibody are administered in 21-day cycles.

In some embodiments, the bispecific antibody is administered at a doseof (or a dose of about) 24 mg. In some embodiments, the bispecificantibody is administered at a dose of (or a dose of about) 48 mg.

In one embodiment, the bispecific antibody is administered once everyweek at a dose of 24 mg or 48 mg (weekly administration/dose), e.g., forthree and one-third 21-day cycles (i.e., day 15 of cycle 1 and days 1,8, and 15 of cycles 2-4). In some embodiments, the bispecific antibodyis administered once every three weeks after the weekly administration,e.g., for two or four 21-day cycles. In some embodiments, the bispecificantibody is administered once every four weeks after the administrationonce every three weeks in 28-day cycles, e.g., for up to one year totalduration of treatment with the bispecific antibody from initiation ofR-CHOP (i.e., from cycle 1). In a further embodiment, a priming dose(e.g., 0.16 mg or about 0.16 mg) of the bispecific antibody isadministered two weeks prior to administering the first weekly dose of24 mg or 48 mg. In some embodiments, after administering the primingdose and prior to administering the weekly dose of 24 mg or 48 mg, anintermediate dose (e.g., 0.8 mg or about 0.8 mg) of the bispecificantibody is administered. In some embodiments, the priming dose isadministered one week before the intermediate dose, and the intermediatedose is administered one week before the first weekly dose of 24 mg or48 mg.

In some embodiments, rituximab is administered in a 21-day cycle onceevery three weeks, e.g., for six or eight 21-day cycles. In someembodiments, rituximab is administered at a dose of 375 mg/m².

In some embodiments, cyclophosphamide is administered in a 21-day cycleonce every three weeks, e.g., for six or eight 21-day cycles. In someembodiments, cyclophosphamide is administered at a dose of 750 mg/m².

In some embodiments, doxorubicin is administered in a 21-day cycle onceevery three weeks, e.g., for six or eight 21-day cycles. In someembodiments, doxorubicin is administered at a dose of 50 mg/m².

In some embodiments, vincristine is administered in a 21-day cycle onceevery three weeks, e.g., for six or eight 21-day cycles. In someembodiments, vincristine is administered at a dose of 1.4 mg/m².

In some embodiments, prednisone is administered once a day from day 1 today 5 of the 21-day cycles, e.g., for six or eight 21-day cycles. Insome embodiments, prednisone is administered at a dose of 100 mg/day.

In some embodiments, rituximab, cyclophosphamide, doxorubicin,vincristine, prednisone, and the bispecific antibody are administered onthe same day (e.g., on day 1 of cycles 1-6 or day 1 of cycles 1-8),e.g., as shown in Table 2.

In some embodiments, administration is performed in 21-day cycles,wherein

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 24 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In some embodiments, administration is performed in 21-day cycles,wherein

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 48 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In one embodiment, the bispecific antibody is administered once everyfour weeks in 28-day cycles from cycle 7, wherein the bispecificantibody is administered on day 1 of each cycle.

In some embodiments, administration is performed in 21-day cycles,wherein

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In some embodiments, administration is performed in 21-day cycles,wherein

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In one embodiment, the bispecific antibody is administered once everyfour weeks in 28-day cycles from cycle 9, wherein the bispecificantibody is administered on day 1 of each cycle.

In some embodiments, the bispecific antibody is administeredsubcutaneously. In some embodiments, rituximab is administeredintravenously. In some embodiments, cyclophosphamide is administeredintravenously. In a further embodiment, doxorubicin is administeredintravenously. In yet a further embodiment, vincristine is administeredintravenously. In some embodiments, prednisone is administeredintravenously or orally.

In some embodiments, the bispecific antibody, rituximab,cyclophosphamide, doxorubicin, and vincristine are administeredsequentially. For example, if administered on the same day, prednisoneis administered first, rituximab is administered second,cyclophosphamide is administered third, doxorubicin is administeredfourth, vincristine is administered fifth, and the bispecific antibodyis administered last.

In some embodiments, the DLBCL is double-hit or triple-hit DLBCL. Insome embodiments, the DLBCL is follicular lymphoma Grade 3B. In someembodiments, the subject has an International Prognostic Index (IPI)score or Revised IPI score ≥3.

In some embodiments, the subject is treated with prophylaxis forcytokine release syndrome (CRS). In some embodiments, the prophylaxiscomprises administering a corticosteroid (e.g., prednisone at a dose of,e.g., 100 mg/day or equivalent thereof, including oral dose) on, forexample, the same day as the bispecific antibody. In some embodiments,the corticosteroid is further administered on the second, third, andfourth days after administering the bispecific antibody. In someembodiments, for the methods described herein involving administeringprednisone as part of the R-CHOP regimen on days 1-5 of each 21-daycycle, no additional prophylaxis for CRS is required, since theprednisone component of R-CHOP serves already as the corticosteroidcomponent of CRS prophylaxis (i.e., there is no double-dosing of thecorticosteroid). However, in such embodiments, a corticosteroid such asprednisone or its equivalent may be administered for CRS prophylaxis ondays for which the bispecific antibody is administered but R-CHOP is notadministered (i.e., prednisone or its equivalent is administered on days8-11 and 15-18 of the first 21-day cycle, and optionally on days 8-11and 15-18 of the second 21-day cycle (or later cycles) if, e.g.,CRS >Grade 1 remains at the end of the previous cycle).

In some embodiments, if the prednisone from R-CHOP is administered morethan 120 minutes before administration of the bispecific antibody, thenthe subject is administered prednisone or an equivalent as CRSprophylaxis about 30-120 minutes prior to administration of thebispecific antibody.

In some embodiments, the subject is administered premedication, such asantihistamine (e.g., diphenhydramine, intravenously or orally at a doseof, e.g., 50 mg or equivalent thereof) and/or antipyretic (e.g.,acetaminophen at a dose of, e.g., 650-1000 mg), to reduce reactions toinjections. In some embodiments, the premedication is administered onthe same day as the bispecific antibody.

In some embodiments, the prophylaxis and premedication are administeredin cycle 1 and start of cycle 2 of the 21-day cycles (i.e., togetherwith the first dose of the bispecific antibody on day 1 in cycle 2). Insome embodiments, the prophylaxis is administered during the second andthird administrations of the bispecific antibody during cycle 2 of the21-day cycles when the subject experiences CRS greater than grade 1after the first administration of the bispecific antibody in cycle 2 ofthe 21-day cycles. In some embodiments, the prophylaxis is continued ina subsequent cycle, when in the last administration of the bispecificantibody of the previous cycle, the subject experiences CRS greater thangrade 1. In a further embodiment, the prophylaxis and premedication areadministered during cycle 2 of the 21-day cycles. In yet a furtherembodiment, the prophylaxis and premedication are administered duringsubsequent cycles.

In some embodiments, the subject is administered antibiotics if thesubject develops Grade 1 CRS. In some embodiments, the subject isadministered a vasopressor if the subject develops Grade 2 or Grade 3CRS. In some embodiments, the subject is administered at least twovasopressors if the subject develops Grade 4 CRS.

In some embodiments, the subject is administered tocilizumab if thesubject develops Grade 2, Grade 3, or Grade 4 CRS. In some embodiments,the subject is further administered a steroid (e.g., dexamethasone ormethylprednisolone). In some embodiments, tocilizumab is switched to ananti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g.,anakinra) if the subject is refractory to tocilizumab.

In some embodiments, the subject is administered prophylaxis for tumorlysis syndrome (TLS). In some embodiments, the prophylaxis for TLScomprises administering one or more uric acid reducing agents prior toadministration of the bispecific antibody. In some embodiments,rasburicase and/or allopurinol is administered as the uric acid reducingagent. In some embodiments, when a subject shows signs of TLS,supportive therapy, such as rasburicase, may be used.

In some embodiments, the subject treated with the methods describedherein achieves a complete response, a partial response, or stabledisease, e.g., as defined by the Lugano criteria or LYRIC.

In some embodiments, the first antigen-binding region of the bispecificantibody comprises VHCDR1, VHCDR2, and VHCDR3 comprising the amino acidsequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, andVLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences set forthin SEQ ID NO: 4, the sequence GTN, and SEQ ID NO: 5, respectively; andthe second antigen-binding region comprises VHCDR1, VHCDR2, and VHCDR3comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and10, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the aminoacid sequences set forth in SEQ ID NO: 11, the sequence DAS, and SEQ IDNO: 12, respectively.

In some embodiments, the first antigen-binding region of the bispecificantibody comprises a VH region comprising the amino acid sequence of SEQID NO: 6, and the VL region comprising the amino acid sequence of SEQ IDNO: 7; and the second antigen-binding region comprises a VH regioncomprising the amino acid sequence of SEQ ID NO: 13, and the VL regioncomprising the amino acid sequence of SEQ ID NO: 14.

In some embodiments, the first binding arm of the bispecific antibody isderived from a humanized antibody, preferably from a full-length IgG1,λ(lambda) antibody (e.g., SEQ ID NO: 22). In some embodiments, the secondbinding arm of the bispecific antibody is derived from a human antibody,preferably from a full-length IgG1,κ (kappa) antibody (e.g., SEQ ID NO:23). In some embodiments, the bispecific antibody is a full-lengthantibody with a human IgG1 constant region.

In some embodiments, the bispecific antibody comprises an inert Fcregion, for example, an Fc region in which the amino acids in thepositions corresponding to positions L234, L235, and D265 in the humanIgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A,respectively. In some embodiments, the bispecific antibody comprisessubstitutions which promote bispecific antibody formation, for example,wherein in the first heavy chain, the amino acid in the positioncorresponding to F405 in the human IgG1 heavy chain constant region ofSEQ ID NO: 15 is L, and wherein in the second heavy chain, the aminoacid in the position corresponding to K409 in the human IgG1 heavy chainconstant region of SEQ ID NO: 15 is R, or vice versa. In someembodiments, the bispecific antibody has both an inert Fc region (e.g.,substitutions at L234, L235, and D265 (e.g., L234F, L235E, and D265A))and substitutions which promote bispecific antibody formation (e.g.,F405L and K409R). In a further embodiment, the bispecific antibodycomprises heavy chain constant regions comprising the amino acidsequences of SEQ ID NOs: 19 and 20.

In some embodiments, the bispecific antibody comprises a first heavychain and a first light chain comprising (or consisting of) the aminoacid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and asecond heavy chain and a second light chain comprising (or consistingof) the amino acid sequences set forth in SEQ ID NOs: 26 and 27,respectively. In some embodiments, the bispecific antibody isepcoritamab, or a biosimilar thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are graphs showing the minimal effects of CHOP components onDuoBody CD3xCD20-induced T-cell-mediated cytotoxicity. FIG. 1A: DuoBodyCD3xCD20+cyclophosphamide, FIG. 1B: DuoBody CD3xCD20+doxorubicin, FIG.1C: DuoBody CD3xCD20+vincristine, FIG. 1D: DuoBody CD3xCD20+prednisone.Left panels show DuoBody CD3xCD20 dose-response curves for onerepresentative donor. Right panels show the results for 4 donors, at 333ng/mL DuoBody CD3xCD20.

FIG. 2 is a schematic of the overall clinical trial design.

FIG. 3 is a schematic of the dose escalation design.

DETAILED DESCRIPTION

The term “immunoglobulin” as used herein refers to a class ofstructurally related glycoproteins consisting of two pairs ofpolypeptide chains, one pair of light (L) low molecular weight chainsand one pair of heavy (H) chains, all four inter-connected by disulfidebonds. The structure of immunoglobulins has been well characterized(see, e.g., Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. RavenPress, N.Y. (1989)). Briefly, each heavy chain typically is comprised ofa heavy chain variable region (abbreviated herein as VH or V_(H)) and aheavy chain constant region (abbreviated herein as CH or C_(H)). Theheavy chain constant region typically is comprised of three domains,CH1, CH2, and CH3. The hinge region is the region between the CH1 andCH2 domains of the heavy chain and is highly flexible. Disulfide bondsin the hinge region are part of the interactions between two heavychains in an IgG molecule. Each light chain typically is comprised of alight chain variable region (abbreviated herein as VL or V_(L)) and alight chain constant region (abbreviated herein as CL or C_(L)). Thelight chain constant region typically is comprised of one domain, CL.The VH and VL regions may be further subdivided into regions ofhypervariability (or hypervariable regions which may be hypervariable insequence and/or form of structurally defined loops), also termedcomplementarity determining regions (CDRs), interspersed with regionsthat are more conserved, termed framework regions (FRs). Each VH and VLis typically composed of three CDRs and four FRs, arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J Mol Biol 1987;196:90117). Unless otherwise stated or contradicted by context, CDRsequences herein are identified according to IMGT rules (Brochet X.,Nucl Acids Res 2008; 36:W503-508; Lefranc M P., Nucl Acids Res 1999;27:209-12; www.imgt.org/). Unless otherwise stated or contradicted bycontext, reference to amino acid positions in the constant regions isaccording to the EU-numbering (Edelman et al., PNAS. 1969; 63:78-85;Kabat et al., Sequences of Proteins of Immunological Interest, FifthEdition. 1991 NIH Publication No. 91-3242). For example, SEQ ID NO: 15sets forth amino acids positions 118-447, according to EU numbering, ofthe IgG1 heavy chain constant region.

The term “amino acid corresponding to position . . . ” as used hereinrefers to an amino acid position number in a human IgG1 heavy chain.Corresponding amino acid positions in other immunoglobulins may be foundby alignment with human IgG1. Thus, an amino acid or segment in onesequence that “corresponds to” an amino acid or segment in anothersequence is one that aligns with the other amino acid or segment using astandard sequence alignment program such as ALIGN, ClustalW or similar,typically at default settings and has at least 50%, at least 80%, atleast 90%, or at least 95% identity to a human IgG1 heavy chain. It iswithin the ability of one of ordinary skill in the art to align asequence or segment in a sequence and thereby determine thecorresponding position in a sequence to an amino acid position accordingto the present invention.

The term “antibody” (Ab) as used herein in the context of the presentinvention refers to an immunoglobulin molecule which has the ability tospecifically bind to an antigen under typical physiological conditionswith a half-life of significant periods of time, such as at least about30 minutes, at least about 45 minutes, at least about one hour, at leastabout two hours, at least about four hours, at least about 8 hours, atleast about 12 hours, about 24 hours or more, about 48 hours or more,about 3, 4, 5, 6, 7 or more days, etc., or any other relevantfunctionally-defined period (such as a time sufficient to induce,promote, enhance, and/or modulate a physiological response associatedwith antibody binding to the antigen and/or time sufficient for theantibody to recruit an effector activity). The variable regions of theheavy and light chains of the immunoglobulin molecule contain a bindingdomain that interacts with an antigen. The term antibody, unlessspecified otherwise, also encompasses polyclonal antibodies, monoclonalantibodies (mAbs), antibody-like polypeptides, chimeric antibodies andhumanized antibodies An antibody as generated can possess any isotype.

The term “antibody fragment” or “antigen-binding fragment” as usedherein refers to a fragment of an immunoglobulin molecule which retainsthe ability to specifically bind to an antigen, and can be generated byany known technique, such as enzymatic cleavage, peptide synthesis, andrecombinant techniques. Examples of antibody fragments include (i) aFab′ or Fab fragment, a monovalent fragment consisting of the VL, VH, CLand CH1 domains, or a monovalent antibody as described in WO2007059782(Genmab); (ii) F(ab′)₂ fragments, bivalent fragments comprising two Fabfragments linked by a disulfide bridge at the hinge region; (iii) a Fdfragment consisting essentially of the VH and CH1 domains; (iv) a Fvfragment consisting essentially of the VL and VH domains of a single armof an antibody, (v) a dAb fragment (Ward et al., Nature 1989; 341:54446), which consists essentially of a VH domain and also called domainantibodies (Holt et al; Trends Biotechnol 2003; 21:484-90); (vi) camelidor nanobodies (Revets et al; Expert Opin Biol Ther 2005; 5:111-24) and(vii) an isolated complementarity determining region (CDR). Furthermore,although the two domains of the Fv fragment, VL and VH, are coded for byseparate genes, they may be joined, using recombinant methods, by asynthetic linker that enables them to be made as a single protein chainin which the VL and VH regions pair to form monovalent molecules (knownas single chain antibodies or single chain Fv (scFv), see, e.g., Bird etal., Science 1988; 242:42326 and Huston et al., PNAS 1988; 85:587983).

Such single chain antibodies are encompassed within the term antibodyfragment unless otherwise noted or clearly indicated by context.

The term “antibody-binding region” or “antigen-binding region” as usedherein refers to the region which interacts with the antigen andcomprises both the VH and the VL regions. The term antibody when usedherein refers not only to monospecific antibodies, but alsomultispecific antibodies which comprise multiple, such as two or more,e.g., three or more, different antigen-binding regions. The termantigen-binding region, unless otherwise stated or clearly contradictedby context, includes fragments of an antibody that are antigen-bindingfragments, i.e., retain the ability to specifically bind to the antigen.

As used herein, the term “isotype” refers to the immunoglobulin class(for instance IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM) that isencoded by heavy chain constant region genes. When a particular isotype,e.g., IgG1, is mentioned, the term is not limited to a specific isotypesequence, e.g., a particular IgG1 sequence, but is used to indicate thatthe antibody is closer in sequence to that isotype, e.g. IgG1, than toother isotypes. Thus, e.g., an IgG1 antibody may be a sequence variantof a naturally-occurring IgG1 antibody, which may include variations inthe constant regions.

The term “bispecific antibody” or “bs” or “bsAb” as used herein refersto an antibody having two different antigen-binding regions defined bydifferent antibody sequences. A bispecific antibody can be of anyformat.

The terms “half molecule”, “Fab-arm”, and “arm”, as used herein, referto one heavy chain-light chain pair.

When a bispecific antibody is described as comprising a half-moleculeantibody “derived from” a first parental antibody, and a half-moleculeantibody “derived from” a second parental antibody, the term “derivedfrom” indicates that the bispecific antibody was generated byrecombining, by any known method, said half-molecules from each of saidfirst and second parental antibodies into the resulting bispecificantibody. In this context, “recombining” is not intended to be limitedby any particular method of recombining and thus includes all of themethods for producing bispecific antibodies described herein, includingfor example recombining by half-molecule exchange (also known as“controlled Fab-arm exchange”), as well as recombining at nucleic acidlevel and/or through co-expression of two half-molecules in the samecells.

The term “full-length” as used herein in the context of an antibodyindicates that the antibody is not a fragment but contains all of thedomains of the particular isotype normally found for that isotype innature, e.g., the VH, CH1, CH2, CH3, hinge, VL and CL domains for anIgG1 antibody. A full-length antibody may be engineered. An example of a“full-length” antibody is epcoritamab.

The term “Fc region” as used herein refers to an antibody regionconsisting of the Fc sequences of the two heavy chains of animmunoglobulin, wherein said Fc sequences comprise at least a hingeregion, a CH2 domain, and a CH3 domain.

The term “heterodimeric interaction between the first and second CH3regions” as used herein refers to the interaction between the first CH3region and the second CH3 region in a first-CH3/second-CH3 heterodimericprotein.

The term “homodimeric interactions of the first and second CH3 regions”as used herein refers to the interaction between a first CH3 region andanother first CH3 region in a first-CH3/first-CH3 homodimeric proteinand the interaction between a second CH3 region and another second CH3region in a second-CH3/second-CH3 homodimeric protein.

The term “isolated antibody” as used herein refers to an antibody whichis substantially free of other antibodies having different antigenicspecificities. In a preferred embodiment, an isolated bispecificantibody that specifically binds to CD20 and CD3 is in additionsubstantially free of monospecific antibodies that specifically bind toCD20 or CD3.

The term “CD3” as used herein refers to the human Cluster ofDifferentiation 3 protein which is part of the T-cell co-receptorprotein complex and is composed of four distinct chains. CD3 is alsofound in other species, and thus, the term “CD3” is not limited to humanCD3 unless contradicted by context. In mammals, the complex contains aCD3γ (gamma) chain (human CD3γ chain UniProtKB/Swiss-Prot No P09693, orcynomolgus monkey CD3γ UniProtKB/Swiss-Prot No Q95LI7), a CD36 (delta)chain (human CD36 UniProtKB/Swiss-Prot No P04234, or cynomolgus monkeyCD36 UniProtKB/Swiss-Prot No Q95LI8), two CD3ε (epsilon) chains (humanCD3ε UniProtKB/Swiss-Prot No P07766, SEQ ID NO: 28); cynomolgus CD3εUniProtKB/Swiss-Prot No Q95LI5; or rhesus CD3ε UniProtKB/Swiss-Prot NoG7NCB9), and a CD3ζ-chain (zeta) chain (human CD3ζ UniProtKB/Swiss-ProtNo P20963, cynomolgus monkey CD3ζ UniProtKB/Swiss-Prot No Q09TK0). Thesechains associate with a molecule known as the T-cell receptor (TCR) andgenerate an activation signal in T lymphocytes. The TCR and CD3molecules together comprise the TCR complex.

The term “CD3 antibody” or “anti-CD3 antibody” as used herein refers toan antibody which binds specifically to the antigen CD3, in particularhuman CD3ε (epsilon).

The term “human CD20” or “CD20” refers to human CD20(UniProtKB/Swiss-Prot No P11836, SEQ ID NO: 29) and includes anyvariants, isoforms, and species homologs of CD20 which are naturallyexpressed by cells, including tumor cells, or are expressed on cellstransfected with the CD20 gene or cDNA. Species homologs include rhesusmonkey CD20 (Macaca mulatta; UniProtKB/Swiss-Prot No H9YXP1) andcynomolgus monkey CD20 (Macaca fascicularis; UniProtKB No G7PQ03).

The term “CD20 antibody” or “anti-CD20 antibody” as used herein refersto an antibody which binds specifically to the antigen CD20, inparticular to human CD20.

The term “CD3xCD20 antibody”, “anti-CD3xCD20 antibody”, “CD20xCD3antibody” or “anti-CD20xCD3 antibody” as used herein refers to abispecific antibody which comprises two different antigen-bindingregions, one of which binds specifically to the antigen CD20 and one ofwhich binds specifically to CD3.

The term “DuoBody-CD3xCD20” as used herein refers to an IgG1 bispecificCD3xCD20 antibody comprising a first heavy and light chain pair asdefined in SEQ ID NO: 24 and SEQ ID NO: 25, respectively, and comprisinga second heavy and light chain pair as defined in SEQ ID NO: 26 and SEQID NO: 27. The first heavy and light chain pair comprises a region whichbinds to human CD3ε (epsilon), the second heavy and light chain paircomprises a region which binds to human CD20. The first binding regioncomprises the VH and VL sequences as defined by SEQ ID NOs: 6 and 7, andthe second binding region comprises the VH and VL sequences as definedby SEQ ID NOs: 13 and 14. This bispecific antibody can be prepared asdescribed in WO 2016/110576.

Antibodies comprising functional variants of the heavy chain, lightchains, VL regions, VH regions, or one or more CDRs of the antibodies ofthe examples as also provided herein. A functional variant of a heavychain, a light chain, VL, VH, or CDRs used in the context of an antibodystill allows the antibody to retain at least a substantial proportion(at least about 90%, 95% or more) of functional features of the“reference” and/or “parent” antibody, including affinity and/or thespecificity/selectivity for particular epitopes of CD20 and/or CD3, Fcinertness and PK parameters such as half-life, Tmax, Cmax. Suchfunctional variants typically retain significant sequence identity tothe parent antibody and/or have substantially similar length of heavyand light chains. The percent identity between two sequences is afunction of the number of identical positions shared by the sequences(i.e., % homology=#of identical positions/total #of positions×100),taking into account the number of gaps, and the length of each gap,which need to be introduced for optimal alignment of the two sequences.The percent identity between two nucleotide or amino acid sequences maye.g. be determined using the algorithm of E. Meyers and W. Miller,Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated intothe ALIGN program (version 2.0), using a PAM120 weight residue table, agap length penalty of 12 and a gap penalty of 4. In addition, thepercent identity between two amino acid sequences may be determinedusing the Needleman and Wunsch, J Mol Biol 1970; 48:444-453 algorithm.Exemplary variants include those which differ from heavy and/or lightchains, VH and/or VL, and/or CDR regions of the parent antibodysequences mainly by conservative substitutions; e.g., 10, such as 9, 8,7, 6, 5, 4, 3, 2 or 1 of the substitutions in the variant may beconservative amino acid residue replacements.

Conservative substitutions may be defined by substitutions within theclasses of amino acids reflected in the following table:

TABLE 1 Amino acid residue classes for conservative substitutions AcidicResidues Asp (D) and Glu (E) Basic Residues Lys (K), Arg (R), and His(H) Hydrophilic Uncharged Residues Ser (S), Thr (T), Asn (N), and Gln(Q) Aliphatic Uncharged Residues Gly (G), Ala (A), Val (V), Leu (L), andIle (I) Non-polar Uncharged Residues Cys (C), Met (M), and Pro (P)Aromatic Residues Phe (F), Tyr (Y), and Trp (W)

Unless otherwise indicated, the following nomenclature is used todescribe a mutation: i) substitution of an amino acid in a givenposition is written as, e.g., K409R which means a substitution of aLysine in position 409 with an Arginine; and ii) for specific variantsthe specific three or one letter codes are used, including the codes Xaaand X to indicate any amino acid residue. Thus, the substitution ofLysine with Arginine in position 409 is designated as: K409R, and thesubstitution of Lysine with any amino acid residue in position 409 isdesignated as K409X. In case of deletion of Lysine in position 409 it isindicated by K409*.

The term “humanized antibody” as used herein refers to a geneticallyengineered non-human antibody, which contains human antibody constantdomains and non-human variable domains modified to contain a high levelof sequence homology to human variable domains. This can be achieved bygrafting of the six non-human antibody CDRs, which together form theantigen binding site, onto a homologous human acceptor framework region(FR) (see WO92/22653 and EP0629240). In order to fully reconstitute thebinding affinity and specificity of the parental antibody, thesubstitution of framework residues from the parental antibody (i.e., thenon-human antibody) into the human framework regions (back-mutations)may be required. Structural homology modeling may help to identify theamino acid residues in the framework regions that are important for thebinding properties of the antibody. Thus, a humanized antibody maycomprise non-human CDR sequences, primarily human framework regionsoptionally comprising one or more amino acid back-mutations to thenon-human amino acid sequence, and fully human constant regions. The VHand VL of the CD3 arm that is used herein in DuoBody-CD3xCD20 representsa humanized antigen-binding region. Optionally, additional amino acidmodifications, which are not necessarily back-mutations, may be appliedto obtain a humanized antibody with preferred characteristics, such asaffinity and biochemical properties.

The term “human antibody” as used herein refers to antibodies havingvariable and constant regions derived from human germline immunoglobulinsequences. Human antibodies may include amino acid residues not encodedby human germline immunoglobulin sequences (e.g., mutations introducedby random or site-specific mutagenesis in vitro or by somatic mutationin vivo). However, the term “human antibody”, as used herein, is notintended to include antibodies in which CDR sequences derived from thegermline of another mammalian species, such as a mouse, have beengrafted onto human framework sequences. The VH and VL of the CD20 armthat is used in DuoBody-CD3xCD20 represents a human antigen-bindingregion. Human monoclonal antibodies of the invention can be produced bya variety of techniques, including conventional monoclonal antibodymethodology, e.g., the standard somatic cell hybridization technique ofKohler and Milstein, Nature 256: 495 (1975). Although somatic cellhybridization procedures are preferred, in principle, other techniquesfor producing monoclonal antibody can be employed, e.g., viral oroncogenic transformation of B-lymphocytes or phage display techniquesusing libraries of human antibody genes. A suitable animal system forpreparing hybridomas that secrete human monoclonal antibodies is themurine system. Hybridoma production in the mouse is a verywell-established procedure. Immunization protocols and techniques forisolation of immunized splenocytes for fusion are known in the art.Fusion partners (e.g., murine myeloma cells) and fusion procedures arealso known. Human monoclonal antibodies can thus be generated using,e.g., transgenic or transchromosomal mice or rats carrying parts of thehuman immune system rather than the mouse or rat system. Accordingly, inone embodiment, a human antibody is obtained from a transgenic animal,such as a mouse or a rat, carrying human germline immunoglobulinsequences instead of animal immunoglobulin sequences. In suchembodiments, the antibody originates from human germline immunoglobulinsequences introduced in the animal, but the final antibody sequence isthe result of said human germline immunoglobulin sequences being furthermodified by somatic hypermutations and affinity maturation by theendogenous animal antibody machinery (see, e.g., Mendez et al. Nat Genet1997; 15:146-56). The VH and VL regions of the CD20 arm that is used inDuoBody-CD3xCD20 represents a human antigen-binding region.

The term “biosimilar” (e.g., of an approved reference product/biologicaldrug) as used herein refers to a biologic product that is similar to thereference product based on data from (a) analytical studiesdemonstrating that the biological product is highly similar to thereference product notwithstanding minor differences in clinicallyinactive components; (b) animal studies (including the assessment oftoxicity); and/or (c) a clinical study or studies (including theassessment of immunogenicity and pharmacokinetics or pharmacodynamics)that are sufficient to demonstrate safety, purity, and potency in one ormore appropriate conditions of use for which the reference product isapproved and intended to be used and for which approval is sought (e.g.,that there are no clinically meaningful differences between thebiological product and the reference product in terms of the safety,purity, and potency of the product). In some embodiments, the biosimilarbiological product and reference product utilizes the same mechanism ormechanisms of action for the condition or conditions of use prescribed,recommended, or suggested in the proposed labeling, but only to theextent the mechanism or mechanisms of action are known for the referenceproduct. In some embodiments, the condition or conditions of useprescribed, recommended, or suggested in the labeling proposed for thebiological product have been previously approved for the referenceproduct. In some embodiments, the route of administration, the dosageform, and/or the strength of the biological product are the same asthose of the reference product. A biosimilar can be, e.g., a presentlyknown antibody having the same primary amino acid sequence as a marketedantibody, but may be made in different cell types or by differentproduction, purification, or formulation methods.

The term “reducing conditions” or “reducing environment” as used hereinrefers to a condition or an environment in which a substrate, here acysteine residue in the hinge region of an antibody, is more likely tobecome reduced than oxidized.

The term “recombinant host cell” (or simply “host cell”) as used hereinis intended to refer to a cell into which an expression vector has beenintroduced, e.g., an expression vector encoding an antibody describedherein. Recombinant host cells include, for example, transfectomas, suchas CHO, CHO-S, HEK, HEK293, HEK-293F, Expi293F, PER.C6 or NS0 cells, andlymphocytic cells.

The term “diffuse large B-cell lymphoma” or “DLBCL” as used hereinrefers to a neoplasm of the germinal center B lymphocytes with a diffusegrowth pattern and a high-intermediate proliferation index. DLBCLrepresents approximately 30% of all lymphomas. Subtypes of DLBCL seem tohave different outlooks (prognoses) and responses to treatment. DLBCLcan affect any age group but occurs mostly in older people (the averageage is mid-60s). “Double hit” and “triple hit” DLBCL refers to DLBCLwith MYC and BCL2 and/or BCL6 translocations, falling under the categoryof high-grade B cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6translocations, in accordance with the WHO 2016 classification (SwerdlowS H, Campo E, Harris N L, et al. WHO Classification of Tumours ofHaematopoietic and Lymphoid Tissues (Revised ed. 4th). Lyon, France:IARC Press (2017), the contents of which are herein incorporated byreference). Follicular lymphoma grade 3B is also often considered to beequivalent to DLBCL and thus treated as such.

The term “R-CHOP” as used herein refers to a drug combination containingrituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.The term “R-CHOP” is also intended to encompass regimens in which therituximab component is replaced with a biosimilar thereof, and/orbranded or generic versions (generic equivalents) of cyclophosphamide,doxorubicin, vincristine, and/or prednisone, as well as pharmaceuticallyacceptable salts, isomers, racemates, solvates, complexes and hydrates,anhydrate forms thereof, and any polymorphic or amorphous forms thereofor combinations thereof, are used in the methods described herein.

The term “rituximab” (CAS Number: 174722-31-7; DrugBank—DB00073; KyotoEncyclopedia of Genes and Genomes (KEGG) entry D02994) as used hereinrefers to a genetically engineered chimeric human gamma 1 murineconstant domain containing monoclonal antibody against human CD20. Thechimeric antibody contains human gamma 1 constant domains and isreferred to as “C2B8” in U.S. Pat. No. 5,736,137 (the entire content ofwhich is herein incorporated by reference). Rituximab is commerciallyavailable, for example, as Rituxan®, MabThera®, or Zytux®. In certainembodiments of the methods described herein, rituximab can be replacedwith a biosimilar thereof. Accordingly, it will be understood that theterm “rituximab” is intended to encompass biosimilars of rituximab. Alsoencompassed by the term “rituximab” are antibodies which have CDRs,variable regions, or heavy and light chains of rituximab. Non-limitingexamples of biosimilars of rituximab include Truxima® (rituximab-abbs),Ruxience® (rituximab-pvvr), and Rixathon®. The biosimilar may beadministered according to a standard of care dosage, or at a doseequivalent to the standard of care dosage specified for rituximab.

The term “cyclophosphamide” as used herein refers to a nitrogen mustardalkylating agent with the chemical name2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-,2-oxide (CAS No. 50-18-0) and has the chemical formula C₇H₁₅Cl₂N₂O₂P. Itis marketed under trade names such as Endoxan®, Cytoxan®, Neosar®,Procytox®, and Revimmune®. The term “cyclophosphamide” is also intendedto encompass branded and generic versions (generic equivalents) ofcyclophosphamide, as well as pharmaceutically acceptable salts, isomers,racemates, solvates, complexes and hydrates, anhydrate forms thereof,and any polymorphic or amorphous forms thereof or combinations thereof.

The term “doxorubicin” as used herein refers to an anthracyclineantibiotic, closely related to the natural product daunomycin, and likeall anthracyclines, it works by intercalating DNA. Doxorubicin ismarketed under trade names such as Adriamycin PFS®, Adriamycin RDF®, orRubex®. Typically, the drug is administered intravenously, in the formof hydrochloride salt (e.g., as doxorubicin hydrochloride). Doxorubicinhydrochloride has the chemical name 5,12-Naphthacenedione,10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-,hydrochloride, (8S,10S)-(CAS No. 25316-40-9), and has the chemicalformula C₂₇H₂₉NO₁₁·HCl. The term “doxorubicin” is also intended toencompass branded and generic versions (generic equivalents) ofdoxorubicin, as well as pharmaceutically acceptable salts, isomers,racemates, solvates, complexes and hydrates, anhydrate forms thereof,and any polymorphic or amorphous forms thereof or combinations thereof.

The term “vincristine” (also known as leurocristine) as used hereinrefers to a vinca alkaloid chemotherapy agent used to treat varioustypes of cancer. It is marketed under trade names such as Oncovin® andVincasar PFS®. Liposomally formulated vincristine sulfate is marketedunder the trade name Marquibo®. The term “vincristine” is also intendedto encompass branded and generic versions (generic equivalents) ofvincristine, as well as pharmaceutically acceptable salts, isomers,racemates, solvates, complexes and hydrates, anhydrate forms thereof,and any polymorphic or amorphous forms thereof or combinations thereof.

“Prednisone” is a synthetic glucocorticoid with anti-inflammatory andimmunosuppressive properties. It is a prodrug that is metabolized in theliver to prednisolone, the active form of the drug. Prednisone ismarketed under trade names such as Deltasone®, Liquid Pred®, Rayos®, andOrasone®, among others. Prednisone has the chemical name17,21-dihydroxypregna-1,4-diene-3,11,20-trione (CAS No. 53-03-2). Theterm “prednisone” is also intended to encompass branded and genericversions (generic equivalents) of prednisone, as well aspharmaceutically acceptable salts, isomers, racemates, solvates,complexes and hydrates, anhydrate forms thereof, and any polymorphic oramorphous forms thereof or combinations thereof.

The term “treatment” refers to the administration of an effective amountof a therapeutically active antibody described herein for the purpose ofeasing, ameliorating, arresting or eradicating (curing) symptoms ordisease states such as DLBCL. Treatment may result in a completeresponse (CR), partial response (PR), or stable disease (SD), forexample, as defined by Lugano criteria and/or LYRIC. Treatment may becontinued, for example, for up to one year total duration of treatmentwith the bispecific antibody from initiation of R-CHOP, or up to diseaseprogression or unacceptable toxicity.

The term “administering” or “administration” as used herein refers tothe physical introduction of a composition (or formulation) comprising atherapeutic agent to a subject, using any of the various methods anddelivery systems known to those skilled in the art. Preferred routes ofadministration for antibodies described herein include intravenous,intraperitoneal, intramuscular, subcutaneous, spinal or other parenteralroutes of administration, for example by injection or infusion. Thephrase “parenteral administration” as used herein means modes ofadministration other than enteral and topical administration, usually byinjection, and includes, without limitation, intravenous,intraperitoneal, intramuscular, intraarterial, intrathecal,intralymphatic, intralesional, intracapsular, intraorbital,intracardiac, intradermal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, epidural andintrasternal injection and infusion, as well as in vivo electroporation.Alternatively, a therapeutic agent described herein can be administeredvia a non-parenteral route, such as a topical, epidermal or mucosalroute of administration, for example, intranasally, orally, vaginally,rectally, sublingually or topically. Administering can also beperformed, for example, once, a plurality of times, and/or over one ormore extended periods. In the methods described herein, the bispecificantibody (e.g., epcoritamab) is administered subcutaneously. Otheragents used in combination with the bispecific antibody, such as forR-CHOP, cytokine release syndrome prophylaxis, and/or tumor lysissyndrome (TLS) prophylaxis, may be administered via other routes, suchas intravenously or orally.

The term “effective amount” or “therapeutically effective amount” refersto an amount effective, at dosages and for periods of time necessary, toachieve a desired therapeutic result. For example, dosages as definedherein for the bispecific antibody (e.g., epcoritamab), i.e., 24 mg or48 mg, administered subcutaneously can be defined as such an “effectiveamount” or “therapeutically effective amount”. A therapeuticallyeffective amount of an antibody may vary according to factors such asthe disease state, age, sex, and weight of the individual, and theability of the antibody to elicit a desired response in the individual.A therapeutically effective amount is also one in which any toxic ordetrimental effects of the antibody or antibody portion are outweighedby the therapeutically beneficial effects. In some embodiments, patientstreated with the methods described herein will show an improvement inECOG performance status. A therapeutically effective amount or dosage ofa drug includes a “prophylactically effective amount” or a“prophylactically effective dosage”, which is any amount of the drugthat, when administered alone or in combination with another therapeuticagent to a subject at risk of developing a disease or disorder (e.g.,cytokine release syndrome) or of suffering a recurrence of disease,inhibits the development or recurrence of the disease.

The term “inhibits growth” of a tumor as used herein includes anymeasurable decrease in the growth of a tumor, e.g., the inhibition ofgrowth of a tumor by at least about 10%, for example, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 99%, or 100%.

The term “subject” as used herein refers to a human patient, forexample, a human patient with DLBCL. The terms “subject” and “patient”are used interchangeably herein.

The term “buffer” as used herein denotes a pharmaceutically acceptablebuffer. The term “buffer” encompasses those agents which maintain the pHvalue of a solution, e.g., in an acceptable range and includes, but isnot limited to, acetate, histidine, TRIS® (tris (hydroxymethyl)aminomethane), citrate, succinate, glycolate and the like. Generally,the “buffer” as used herein has a pKa and buffering capacity suitablefor the pH range of about 5 to about 6, preferably of about 5.5.

“Disease progression” or “PD” as used herein refers to a situation inwhich one or more indices of DLBCL show that the disease is advancingdespite treatment. In one embodiment, disease progression is definedbased on the Lugano Response Criteria for Malignant Lymphoma (“Luganocriteria”) and/or Lymphoma Response to Immunomodulatory Therapy Criteria(LYRIC). Details regarding the Lugano criteria/classification system,including definitions for complete response (CR), partial response (PR),no response/stable disease (NR/SD), and progressive disease (PD) areprovided in Cheson et al. J Clin Oncol 2014; 32:3059-68, the contents ofwhich are incorporated by reference herein (see, in particular, Table 3in Cheson et al., 2014). Details regarding LYRIC are provided in Table11.

A “surfactant” as used herein is a compound that is typically used inpharmaceutical formulations to prevent drug adsorption to surfaces andor aggregation. Furthermore, surfactants lower the surface tension (orinterfacial tension) between two liquids or between a liquid and asolid. For example, an exemplary surfactant can significantly lower thesurface tension when present at very low concentrations (e.g., 5% w/v orless, such as 3% w/v or less, such as 1% w/v or less such as 0.4% w/v orless, such as below 0.1% w/v or less, such as 0.04% w/v). Surfactantsare amphiphilic, which means they are usually composed of bothhydrophilic and hydrophobic or lipophilic groups, thus being capable offorming micelles or similar self-assembled structures in aqueoussolutions. Known surfactants for pharmaceutical use include glycerolmonooleate, benzethonium chloride, sodium docusate, phospholipids,polyethylene alkyl ethers, sodium lauryl sulfate and tricaprylin(anionic surfactants); benzalkonium chloride, citrimide, cetylpyridiniumchloride and phospholipids (cationic surfactants); and alpha tocopherol,glycerol monooleate, myristyl alcohol, phospholipids, poloxamers,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene sorbintan fatty acid esters, polyoxyethylene sterarates,polyoxyl hydroxystearate, polyoxylglycerides, polysorbates such aspolysorbate 20 or polysorbate 80, propylene glycol dilaurate, propyleneglycol monolaurate, sorbitan esters sucrose palmitate, sucrose stearate,tricaprylin and TPGS (Nonionic and zwitterionic surfactants).

A “diluent” as used herein is one which is pharmaceutically acceptable(safe and non-toxic for administration to a human) and is useful for thepreparation of dilutions of the pharmaceutical composition orpharmaceutical formulation (the terms “composition” and “formulation”are used interchangeably herein). Preferably, such dilutions of thecomposition dilute only the antibody concentration but not the bufferand stabilizer. Accordingly, in one embodiment, the diluent contains thesame concentrations of the buffer and stabilizer as is present in thepharmaceutical composition of the invention. Further exemplary diluentsinclude sterile water, bacteriostatic water for injection (BWFI), a pHbuffered solution which is preferably an acetate buffer, sterile salinesolution such as water for injection, Ringer's solution or dextrosesolution. In one embodiment the diluent comprises or consistsessentially of acetate buffer and sorbitol.

As used herein, the term “about” refers to a value that is no more than10% above and no more than 10% below a specified value.

DLBCL Treatment Regimens

Provided herein are methods of treating DLBCL in a human subject using abispecific antibody which binds to CD3 and CD20 (“anti-CD3xCD20antibody”), e.g., an isolated anti-CD3xCD20 antibody such as epcoritamabwhich binds to human CD3 and human CD20, in combination with a standardof care regimen of R-CHOP (i.e., rituximab, cyclophosphamide,doxorubicin, vincristine, and prednisone). The methods are useful fortreating, e.g., previously untreated, high-risk (IPI or R-IPI ≥3) DLBCL.It is understood that the methods of treating DLBCL (e.g.,newly-diagnosed, previously untreated, high-risk (IPI or R-IPI 3-5)DLBCL) with a bispecific antibody which binds to both CD3 and CD20described herein also encompass corresponding uses of the bispecificantibody for treating DLBCL (e.g., newly-diagnosed, previouslyuntreated, high-risk (IPI or R-IPI 3-5) DLBCL) in a human subject.

Accordingly, in one aspect, provided herein is a method of treatingDLBCL in a human subject, the method comprising administering abispecific antibody and an effective amount of (a) rituximab, (b)cyclophosphamide, (c) doxorubicin, (d) vincristine, and (e) prednisone,wherein the bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a        variable heavy chain (VH) region and a variable light chain (VL)        region, wherein the VH region comprises the CDR1, CDR2 and CDR3        sequences that are in the VH region sequence of SEQ ID NO: 6,        and the VL region comprises the CDR1, CDR2 and CDR3 sequences        that are in the VL region sequence of SEQ ID NO: 7; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region and a        VL region, wherein the VH region comprises the CDR1, CDR2 and        CDR3 sequences that are in the VH region sequence of SEQ ID NO:        13, and the VL region comprises the CDR1, CDR2 and CDR3        sequences that are in the VL region sequence of SEQ ID NO: 14;    -   wherein the bispecific antibody is administered at a dose of 24        mg or 48 mg, and wherein rituximab, cyclophosphamide,        doxorubicin, vincristine, prednisone, and the bispecific        antibody are administered in 21-day cycles.

In some embodiments, the bispecific antibody is a full-length antibody.In some embodiments, the bispecific antibody is an antibody with aninert Fc region. In some embodiments, the bispecific antibody is afull-length antibody with an inert Fc region.

In some embodiments, the bispecific antibody is administered at a doseof (or a dose of about) 24 mg. In some embodiments, the bispecificantibody is administered at a dose of (or a dose of about) 48 mg.

With regard to the dose of (or dose of about) 24 mg or 48 mg of thebispecific antibody that is to be administered, or any other specifieddose, it is understood that this amount refers to the amount of abispecific antibody representing a full-length antibody, such asepcoritamab as defined in the Examples section. Hence, one may refer toadministering a dose of a bispecific antibody of 24 mg as administeringa dose of a bispecific antibody described herein, wherein the dosecorresponds to a dose of 24 mg of epcoritamab. One of ordinary skill inthe art can readily determine the amount of antibody to be administeredwhen, for example, the antibody used differs substantially in molecularweight from the molecular weight of a full-length antibody such asepcoritamab. For instance, the amount of antibody can be calculated bydividing the molecular weight of the antibody by the weight of afull-length antibody such as epcoritamab and multiplying the outcomethereof with the specified dose as described herein. As long as thebispecific antibody (e.g., a functional variant of DuoBody CD3xCD20) hashighly similar features as DuoBody CD3xCD20, with regard to plasmahalf-life, Fc inertness, and/or binding characteristics for CD3 andCD20, i.e., with regard to CDRs and epitope binding features, suchantibodies are suitable for use in the methods provided herein at a dosedescribed for a full-length antibody such as epcoritamab.

In some embodiments, the dose of bispecific antibody is administeredonce every week (weekly administration) in 21-day cycles. In oneembodiment, the weekly dose of 24 mg or 48 mg is administered for threeand one-third 21-day cycles (i.e., 10 times; on day 15 of cycle 1, anddays 1, 8, and 15 of cycles 2-4). In one embodiment, the weekly dose of24 mg is administered for three and one-third 21-day cycles (i.e., 10times; on day 15 of cycle 1, and days 1, 8, and 15 of cycles 2-4). Inone embodiment, the weekly dose of 48 mg is administered for three andone-third 21-day cycles (i.e., 10 times; on day 15 of cycle 1, and days1, 8, and 15 of cycles 2-4). In some embodiments, after the weeklyadministration, one may reduce the interval of administration to onceevery three weeks. In one embodiment, the administration once everythree weeks is performed for two or four 21-day cycles (i.e., two orfour times, respectively). In one embodiment, the administration onceevery three weeks is performed for two 21-day cycles (i.e., two times).In one embodiment, the administration once every three weeks isperformed for four 21-day cycles (i.e., two times). In some embodiments,after the administration once every three weeks in 21-day cycles, onemay reduce the interval of administration to once every four weeks in28-day cycles i.e. after the administration once every three weeks, thebispecific antibody is administered once every four weeks in 28-daycycles. In some embodiments, the administration once every four weeks in28-day cycles is performed for up to one year total duration oftreatment with the bispecific antibody. In one embodiment, theadministration once every four weeks in 28-day cycles may be performedfor an extended period, for example, for at least 1 cycle, at least 2cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, atleast 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles,at least 10 cycles, at least 11 cycles, at least 12 cycles, at least 13cycles, at least 14 cycles, at least 15 cycles, or between 1-20 cycles,1-19 cycles, 1-18 cycles, 1-17 cycles, 1-16 cycles, 1-15 cycles, 1-14cycles, 1-13 cycles, 1-12 cycles, 1-10 cycles, 1-5 cycles, 5-20 cycles,5-15 cycles, 5-10 cycles 10-20 cycles, 10-15 cycles, or 15-20 cycles. Insome embodiments, the bispecific antibody is administered once everyfour weeks from cycle 7 or cycle 9 (i.e., cycle starting after thebispecific antibody+R-CHOP combination has ended) to cycle 17 of the28-day cycles. In some embodiments, the bispecific antibody isadministered once every four weeks from cycle 7 or cycle 9 for up to oneyear total duration of treatment with the bispecific antibody frominitiation of R-CHOP. In a further embodiment, the bispecific antibodyis administered from cycle 7 or cycle 9 of the 28-day cycles untildisease progression (e.g., as defined by the Lugano criteria or LYRIC)or unacceptable toxicity.

In one embodiment, the weekly dose of the bispecific antibody isadministered in 21-day cycles on cycles 1-4 (which may include primingand intermediate doses, as described below), the dose once every threeweeks of the bispecific antibody is administered in 21-day cycles oncycles 5-6 or 5-8, and the dose once every four weeks is administered in28-day cycles from cycle 7 or 9 onwards, for example, on cycles 7-17 or9-17, or more cycles, e.g., for up to one year total duration oftreatment with the bispecific antibody from initiation of R-CHOP, oruntil disease progression or unacceptable toxicity is observed in thesubject. In some embodiments, the dose once every four weeks in 28-daycycles is administered on cycles 7-17 or 9-17.

It is understood that the doses referred to herein may also be referredto as a full or a flat dose in the scenarios above wherein, e.g., theweekly dose, dose once every three weeks, and/or the dose every fourweeks is administered at the same level. Accordingly, when a dose of 48mg is selected, preferably, at each weekly administration, at eachadministration once every three weeks, and each administration everyfour weeks, the same dose of 48 mg is administered. Prior toadministering the dose, a priming or a priming and subsequentintermediate (second priming) dose may be administered. This may beadvantageous as it may help mitigate cytokine release syndrome (CRS)risk and severity, a side-effect that can occur during treatment withthe bispecific anti-CD3xCD20 antibody described herein. Such priming, orpriming and intermediate doses, are at a lower dose as compared with theflat or full dose.

Accordingly, in some embodiments, prior to administering the weekly doseof 24 mg or 48 mg, a priming dose of the bispecific antibody may beadministered. In one embodiment, the priming dose is administered twoweeks prior to administering the first weekly dose of 24 mg or 48 mg incycle 1. In one embodiment, the priming dose is 0.16 mg (or about 0.16mg) of the full-length bispecific antibody. In one embodiment, thepriming dose of 0.16 mg is administered two weeks prior to administeringthe first weekly dose of 24 mg in cycle 1. In one embodiment, thepriming dose of 0.16 mg is administered two weeks prior to administeringthe first weekly dose of 48 mg in cycle 1.

In some embodiments, after administering the priming dose and prior toadministering the weekly dose of 24 mg or 48 mg, an intermediate dose ofsaid bispecific antibody is administered. In one embodiment, the primingdose is administered one week before the intermediate dose (i.e., on day1 of cycle 1), and the intermediate dose is administered one week beforethe first weekly dose of 24 mg or 48 mg (i.e., on day 8 of cycle 1).Thus, the priming dose is administered on day 1 and the intermediatedose is administered on day 8 before the first weekly dose of 24 mg or48 mg on day 15 of cycle. In one embodiment, the intermediate dose is800 μg (0.8 mg) or about 800 μg (0.8 mg) of the full-length bispecificantibody. In one embodiment, the priming dose of 0.16 mg is administeredone week before the intermediate dose (i.e., on day 1 of cycle 1) of 0.8mg, and the intermediate dose is administered one week before the firstweekly dose of 24 mg (i.e., on day 8 of cycle 1). In one embodiment, thepriming dose of 0.16 mg is administered one week before the intermediatedose (i.e., on day 1 of cycle 1) of 0.8 mg, and the intermediate dose isadministered one week before the first weekly dose of 48 mg (i.e., onday 8 of cycle 1).

The methods described herein involve treating human subjects who haveDLBCL with a bispecific antibody which binds to CD3 and CD20 incombination with a standard-of-care regimen of rituximab,cyclophosphamide, doxorubicin, vincristine, and prednisone.

In some embodiments, rituximab, cyclophosphamide, doxorubicin,vincristine, and prednisone are administered at standard-of-care dosagesfor R-CHOP, e.g., as supported by clinical studies, according to localguidelines, and/or according to relevant local labels.

For example, in some embodiments, rituximab is administered according torelevant local product labels or summary of product characteristics(see, e.g., RITUXAN® (rituximab) prescribing information, available atwww.accessdata.fda.gov/drugsatfda_docs/label/2013/103705s54141b1.pdf).In some embodiments, a biosimilar of rituximab is used in place ofrituximab in the methods described herein.

In some embodiments, cyclophosphamide is administered according torelevant local product labels or summary of product characteristics(see, e.g., CYCLOPHOSPHAMIDE injection prescribing information,available atwww.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s1121b1.pdf).

In some embodiments, doxorubicin is administered according to relevantlocal product labels or summary of product characteristics (see, e.g.,ADRIAMYCIN (DOXOrubicin HCl) for Injection (lyophilized) and ADRIAMYCIN(DOXOrubicin HCL) Injection (0.9% sodium chloride and water) prescribinginformation, available atwww.accessdata.fda.gov/drugsatfda_docs/label/2012/062921s0221b1.pdf,Doxorubicin Hydrochloride for Injection and Doxorubicin HydrochlorideInjection prescribing information available atwww.accessdata.fda.gov/drugsatfda_docs/label/2010/050467s0701b1.pdf).

In some embodiments, vincristine is administered according to relevantlocal product labels or summary of product characteristics (see, e.g.,VinCRIStine Sulfate Injection prescribing information, available atwww.accessdata.fda.gov/drugsatfda_docs/label/2014/071484s0421b1.pdf).

In some embodiments, prednisolone is administered in place of prednisonein the R-CHOP regimen.

In one embodiment, rituximab is administered according to localguidelines and local labels. In some embodiments, rituximab isadministered at a dose of (or a dose of about) 375 mg/m². In someembodiments, rituximab is administered intravenously.

In one embodiment, rituximab is administered once every three weeks. Insome embodiments, rituximab is administered once every three weeks (Q3W) in 21-day cycles. In some embodiments, administration of rituximabonce every three weeks is performed for six or eight 21-day cycles(i.e., six or eight times, respectively). In preferred embodiments,rituximab is administered intravenously once every three weeks for six21-day cycles (i.e., six times) at a dose of 375 mg/m². In preferredembodiments, rituximab is administered intravenously once every threeweeks for eight 21-day cycles (i.e., eight times) at a dose of 375mg/m².

In some embodiments, cyclophosphamide is administered according to localguidelines and local labels. In some embodiments, cyclophosphamide isadministered at a dose of (or a dose of about) 750 mg/m². In someembodiments, cyclophosphamide is administered intravenously. In someembodiments, cyclophosphamide is administered once every three weeks. Insome embodiments, rituximab is administered once every three weeks (Q3W) in 21-day cycles. In some embodiment, administration ofcyclophosphamide once every three weeks is performed for six or eight21-day cycles (i.e., six or eight times, respectively). In a preferredembodiment, cyclophosphamide is administered intravenously once everythree weeks for six 21-day cycles (i.e., six times) at a dose of 750mg/m². In another preferred embodiment, cyclophosphamide is administeredintravenously once every three weeks for eight 21-day cycles (i.e.,eight times) at a dose of 750 mg/m².

In some embodiments, doxorubicin is administered according to localguidelines and local labels. In some embodiments, doxorubicin isadministered at a dose of (or a dose of about) 50 mg/m². In someembodiments, doxorubicin is administered intravenously. In someembodiments, doxorubicin is administered once every three weeks. In someembodiments, doxorubicin is administered once every three weeks (Q3 W)in 21-day cycles. In some embodiments, administration of doxorubicinonce every three weeks is performed for six or eight 21-day cycles(i.e., six or eight times, respectively). In a preferred embodiment,doxorubicin is administered intravenously once every three weeks for six21-day cycles (i.e., six times) at a dose of 50 mg/m². In anotherpreferred embodiment, doxorubicin is administered intravenously onceevery three weeks for eight 21-day cycles (i.e., eight times) at a doseof 50 mg/m².

In some embodiments, vincristine is administered according to localguidelines and local labels. In some embodiments, vincristine isadministered at a dose of (or a dose of about) 1.4 mg/m². In someembodiments, the maximum dose of vincristine administered to the subjectis below 2 mg. In a further embodiment, vincristine is administeredintravenously. In some embodiments, vincristine is administered onceevery three weeks. In some embodiments, vincristine is administered onceevery three weeks (Q3 W) in 21-day cycles. In some embodiments,administration of vincristine once every three weeks is performed forsix or eight 21-day cycles (i.e., six or eight times). In a preferredembodiment, vincristine is administered intravenously once every threeweeks for six 21-day cycles (i.e., six times) at a dose of less than 2mg/m². In another preferred embodiment, vincristine is administeredintravenously once every three weeks for eight 21-day cycles (i.e.,eight times) at a dose of less than 2 mg/m². In a most preferredembodiment, vincristine is administered intravenously once every threeweeks for six 21-day cycles (i.e., six times) at a dose of 1.4 mg/m². Inanother most preferred embodiment, vincristine is administeredintravenously once every three weeks for eight 21-day cycles (i.e.,eight times) at a dose of 1.4 mg/m².

In a preferred embodiment, rituximab is preferably administered at adose of 375 mg/m², cyclophosphamide is preferably administered at a doseof 750 mg/m², doxorubicin is preferably administered at a dose of 50mg/m², vincristine is preferably administered at a dose of 1.4 mg/m²,wherein rituximab, cyclophosphamide, doxorubicin and vincristine ispreferably administered intravenously once every three weeks for six21-day cycles.

In some embodiments, prednisone is administered according to localguidelines and local labels. In some embodiments, prednisone isadministered at a dose of (or a dose of about) 100 mg. In someembodiment, prednisone is administered intravenously and/or orally. Insome embodiments, prednisone is administered intravenously. In someembodiments, prednisone is administered orally.

In one embodiment, prednisone is administered once a day for fiveconsecutive days (i.e., days 1-5) in 21-day cycles. In one embodiment,prednisone is administered for six or eight 21-day cycles (e.g., on days1-5 of cycles 1-6 or cycles 1-8 of the 21-day cycles). In oneembodiment, prednisone is administered once a day on days 1-5 in 21-daycycles. In some embodiments, prednisone is administered once a day forfive consecutive days (i.e., days 1-5) for six or eight 21-day cycles(e.g., on days 1-5 of cycles 1-6 or cycles 1-8 of the 21-day cycles). Ina preferred embodiment, prednisone is administered intravenously once aday for five consecutive days (i.e., days 1-5) for six 21-day cycles(e.g., on days 1-5 of cycles 1-6 of the 21-day cycles) at a dose of 100mg/day. In another preferred embodiment, prednisone is administeredintravenously once a day for five consecutive days (i.e., days 1-5) foreight 21-day cycles (e.g., on days 1-5 of cycles 1-8 of the 21-daycycles) a dose of 100 mg/day. In another preferred embodiment,prednisone is administered orally once a day for five consecutive days(i.e., days 1-5) for six 21-day cycles (e.g., on days 1-5 of cycles 1-6of the 21-day cycles) at a dose of 100 mg/day. In another preferredembodiment, prednisone is administered orally once a day for fiveconsecutive days (i.e., days 1-5) for eight 21-day cycles (e.g., on days1-5 of cycles 1-8 of the 21-day cycles) a dose of 100 mg/day. In anotherpreferred embodiment, prednisone is administered intravenously and/ororally once a day for five consecutive days (i.e., days 1-5) for six21-day cycles (e.g., on days 1-5 of cycles 1-6 of the 21-day cycles) ata dose of 100 mg/day. In another preferred embodiment, prednisone isadministered intravenously and/or orally once a day for five consecutivedays (i.e., days 1-5) for eight 21-day cycles (e.g., on days 1-5 ofcycles 1-8 of the 21-day cycles) a dose of 100 mg/day. In oneembodiment, the dose of cyclophosphamide or doxorubicin is reduced whena subject presents with cyclophosphamide- or doxorubicin-relatedhematological toxicities during a treatment cycle in accordance withstandard of care guidelines, for example, as specified in the productlabel. See, for example, Table 8 for dose modification criteria orcyclophosphamide and doxorubicin (see also Table 9).

In one embodiment, the dose of vincristine is reduced when a subjectpresents with impaired hepatic function, e.g., using serum bilirubinlevels as a marker. For example, if a subject has serum bilirubin levelsof 2-3 mg/dL, then the dose of vincristine is reduced to 75% of thenormal dose. If a subject has serum bilirubin levels of >3.0 mg/dL, thenthe dose of vincristine is reduced to 50% of the normal dose.Vincristine can be re-escalated when hyperalbuminemia improves.

In one embodiment, the dose of prednisone (or equivalent) is reducedaccording to local prescribing information. For example, when a subjectdevelops an adverse event related to corticosteroid and cannot toleratethe 100 mg/day dose (or equivalent), then the dose may be reduced to noless than 80 mg/day. In some embodiments, the dose reduction ofprednisone (or equivalent) is performed in a tapering regimen.

In certain embodiments, the bispecific antibody, rituximab,cyclophosphamide, doxorubicin, vincristine, and prednisone areadministered simultaneously.

In other embodiments, the bispecific antibody, rituximab,cyclophosphamide, doxorubicin, vincristine, and prednisone areadministered sequentially. For instance, in some embodiments, thebispecific antibody, rituximab, cyclophosphamide, doxorubicin,vincristine, and prednisone are administered on the same day. In oneembodiment, when the bispecific antibody and R-CHOP are administered onthe same day, prednisone is administered first, rituximab isadministered second, cyclophosphamide is administered third, doxorubicinis administered fourth, vincristine is administered fifth, and thebispecific antibody is administered last.

In some embodiments, the subject is administered premedication and/orprophylaxis for CRS prior to administration of rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, and thebispecific antibody. In one embodiment, the prednisone component of theR-CHOP regimen is used as the corticosteroid in CRS prophylaxis.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody (e.g., subcutaneous) are administered in 21-day cycles,wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-6, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody (e.g., subcutaneous) are administered in 21-day cycles,wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-6, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In the two embodiments above, the bispecific antibody is administeredonce every four weeks in 28-day cycles from cycle 7 (e.g., from cycle7-cycle 15, from cycle 7 to cycle 17, from cycle 7 to cycle 20, or fromcycle 7 up to one year total duration of treatment with the bispecificantibody from initiation of R-CHOP). In the two embodiments above,rituximab is preferably administered at a dose of 375 mg/m²,cyclophosphamide is preferably administered at a dose of 750 mg/m²,doxorubicin is preferably administered at a dose of 50 mg/m²,vincristine is preferably administered at a dose of 1.4 mg/m² andprednisone is preferably administered at a dose of 100 mg/day.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody (e.g., subcutaneous) are administered in 21-day cycles,wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody (e.g., subcutaneous) are administered in 21-day cycles,wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In the two embodiments above, the bispecific antibody is administeredonce every four weeks in 28-day cycles from cycle 9 (e.g., from cycle9-cycle 15, from cycle 9 to cycle 17, from cycle 9 to cycle 20, or forup to one year total duration of treatment with the bispecific antibodyfrom initiation of R-CHOP). In the two embodiments above, rituximab ispreferably administered at a dose of 375 mg/m², cyclophosphamide ispreferably administered at a dose of 750 mg/m², doxorubicin ispreferably administered at a dose of 50 mg/m², vincristine is preferablyadministered at a dose of 1.4 mg/m² and prednisone is preferablyadministered at a dose of 100 mg/day.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody epcoritamab (e.g., subcutaneous) are administered in 21-daycycles, wherein:

-   -   (a) the bispecific antibody epcoritamab is administered as        follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-6, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody epcoritamab (e.g., subcutaneous) are administered in 21-daycycles, wherein:

-   -   (a) the bispecific antibody epcoritamab is administered as        follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-6, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

In the two embodiments above, the bispecific antibody epcoritamab isfurther administered once every four weeks in 28-day cycles from cycle 7(e.g., from cycle 7-cycle 15, from cycle 7 to cycle 17, from cycle 7 tocycle 20, or from cycle 9 up to one year total duration of treatmentwith the bispecific antibody from initiation of R-CHOP). In the twoembodiments above, rituximab is preferably administered at a dose of 375mg/m², cyclophosphamide is preferably administered at a dose of 750mg/m², doxorubicin is preferably administered at a dose of 50 mg/m²,vincristine is preferably administered at a dose of 1.4 mg/m² andprednisone is preferably administered at a dose of 100 mg/day.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody epcoritamab (e.g., subcutaneous) are administered in 21-daycycles, wherein:

-   -   (a) the bispecific antibody epcoritamab is administered as        follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In one embodiment, rituximab (e.g., intravenous), cyclophosphamide(e.g., intravenous), doxorubicin (e.g., intravenous), vincristine (e.g.,intravenous), prednisone (e.g., intravenous or oral), and the bispecificantibody epcoritamab (e.g., subcutaneous) are administered in 21-daycycles, wherein:

-   -   (a) the bispecific antibody epcoritamab is administered as        follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

In the two embodiments above, the bispecific antibody epcoritamab isfurther administered once every four weeks in 28-day cycles from cycle 9(e.g., from cycle 9-cycle 15, from cycle 9 to cycle 17, from cycle 9 tocycle 20, or from cycle 9 up to one year total duration of treatmentwith the bispecific antibody from initiation of R-CHOP). In the twoembodiments above, rituximab is preferably administered at a dose of 375mg/m², cyclophosphamide is preferably administered at a dose of 750mg/m², doxorubicin is preferably administered at a dose of 50 mg/m²,vincristine is preferably administered at a dose of 1.4 mg/m² andprednisone is preferably administered at a dose of 100 mg/day.

In some embodiments, subjects considered to be at risk of thrombosis areadministered prophylactic antithrombotic treatment, such as low-doseaspirin (e.g., 70-100 mg daily). In certain embodiments, subjects with aprior history of deep vein thrombosis (DVT) or pulmonary embolism (PE)are administered anticoagulation therapy.

In one embodiment, the subject undergoing the treatment with the methodsdescribed herein has documented DLBCL (de novo or histologicallytransformed from indolent lymphomas, except for CLL) according to theWHO 2016 classification. Accordingly, in one embodiment, the subject hasDLBCL, NOS (not otherwise specified). In some embodiments, the subjecthas “double hit” or “triple hit” DLBCL, which are classified in WHO 2016as HGBCL, with MYC and BCL2 and/or BCL6 translocations. In someembodiments, the subject has follicular lymphoma Grade 3B.

In one embodiment, the subject with DLBCL has a Revised InternationalPrognostic Index (R-IPI) score ≥3, such as an R-IPI score of 3, 4, or 5.IPI risk factors include (1) Ann Arbor Stage III or IV, (2) age >60years, (3) Lactate dehydrogenase level elevated, (4) ECOG performancescore ≥2, and (5) more than 1 extranodal site. R-IPI scoring is based onthe number of above risk factors (1)-(5). R-IPI risk groups arecategorized as Very good (0 IPI risk factors), Good (1 or 2 IPI riskfactors), and Poor (3-5 IPI risk factors). R-IPI applies to subjectswith newly diagnosed DLBCL who are receiving R-CHOP as first-linetherapy. See, e.g., Information regarding the R-IPI is available, e.g.,in Sehn et al., Blood 2007; 109:1857-71.

In one embodiment, the subject with DLBCL has not received prior therapyfor DLBCL or follicular lymphoma Grade 3B.

In one embodiment, the subject has an Eastern Cooperative Oncology Group(ECOG) performance status (ECOG PS) of 0, 1, or 2. Information regardingECOG PS scores can be found in, e.g., Oken et al, Am J Clin Oncol 1982December; 5(6):649-55).

In one embodiment, the subject has measurable disease as defined as (a)≥1 measurable nodal lesion (long axis >1.5 cm and short axis >1.0 cm) or≥1 measurable extra-nodal lesion (long axis >1 cm) on CT or MRI.

In some embodiments, the subject has acceptable organ function asdefined as: (a) ANC ≥1.0×10⁹/L, (b) platelet count >75×10⁹/L, or≥50×10⁹/L if bone marrow infiltration or splenomegaly, (c) ALT level≤2.5 times the ULN, (d) total bilirubin level ≤2×ULN, (e) eGFR >50mL/min (by Cockcroft-Gault Formula), and (f) PT, INR, and aPTT ≤1.5×ULN(unless receiving anticoagulant).

In one embodiment, the subject does not have severe allergic oranaphylactic reactions to anti-CD20 antibody therapy, any component ofCHOP (i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone),or the bispecific antibody, or known allergy or intolerance to anycomponent or excipient of rituximab, CHOP, and/or the bispecificantibody.

In one embodiment, the subject has not received prior therapy for DLBCL(with the exception of nodal biopsy). In some embodiments, the subjectdoes not have a contraindication to any individual drug in the R-CHOPregimen.

In one embodiment, the subject does not have clinically significantcardiac disease, including (a) myocardial infarction within one yearprior to the first dose of the bispecific antibody, or unstable oruncontrolled disease/condition related to or affecting cardiac function(e.g., unstable angina, congestive heart failure, NYHA class III-IV),cardiac arrhythmia (CTCAE Version 4 Grade 2 or higher), or clinicallysignificant ECG abnormalities, and/or (b) 12-lead ECG showing a baselineQTcF >470 msec.

A human subject receiving a treatment described herein may be a patienthaving one or more of the inclusion criteria set forth in Example 3, ornot having one or more of the exclusion criteria set forth in Example 3.

The methods described herein are advantageous for treating DLBCL, suchas previously untreated, high risk (IPI or R-IPI ≥3) DLBCL. Thetreatment is maintained continuously using, e.g., the treatment regimensdescribed herein. However, treatment may be terminated when progressivedisease develops or unacceptable toxicity occurs.

The response of subjects with DLBCL to treatment using the methodsdescribed herein may be assessed according to the Lugano ResponseCriteria for Malignant Lymphoma (also referred to as “Lugano criteria”herein) and/or Lymphoma Response to Immunomodulatory Therapy Criteria(also referred to as “LYRIC” herein), as described in Example 3. In oneembodiment, complete response (CR), partial response (PR), and stabledisease (SD) are assessed using the Lugano criteria. In someembodiments, patients showing disease progression, also referred to asprogressive disease (PD), according to the Lugano criteria are furtherevaluated according to LYRIC. Details regarding the Luganocriteria/classification system, including definitions for completeresponse, partial response, no response/stable disease, and progressivedisease are provided in Cheson et al. J Clin Oncol 2014; 32:3059-68(see, in particular, Table 3 in Cheson et al., 2014). Details regardingLYRIC are provided in Table 11.

In some embodiments, subjects are treated with the methods describedherein until they show disease progression (PD), e.g., as defined byLugano criteria and/or LYRIC. In one embodiment, subjects are treatedwith the methods described herein until they show disease progression(PD) as defined by both Lugano criteria and LYRIC. In some embodiments,the subjects are treated with the methods described herein for up to oneyear total duration of treatment with the bispecific antibody frominitiation of R-CHOP.

Subjects treated according to the methods described herein preferablyexperience improvement in at least one sign of DLBCL. In one embodiment,improvement is measured by a reduction in the quantity and/or size ofmeasurable tumor lesions. In some embodiments, lesions can be measuredon CT, PET-CT, or MRI films. In some embodiments, cytology or histologycan be used to evaluate responsiveness to a therapy. In someembodiments, bone marrow aspirate and bone marrow biopsy can be used toevaluate response to therapy.

In one embodiment, the subject treated exhibits a complete response(CR), a partial response (PR), or stable disease (SD), as defined by theLugano criteria and/or LYRIC (see, e.g., Table 11). In some embodiments,the methods described herein produce at least one therapeutic effectchosen from prolonged survival, such as progression-free survival oroverall survival, optionally compared to another therapy or placebo.

Cytokine release syndrome (CRS) can occur when methods are used in humansubjects that utilize immune cell- and bispecific antibody-basedapproaches that function by activation of immune effector cell, such asby engaging CD3 (Lee et al., Biol Blood Marrow Transplant 2019;25:625-38, which is incorporated herein by reference). Hence, in someembodiments, CRS mitigation is performed together with the methodsdescribed herein. As part of CRS mitigation, the selection of a primingdose and/or intermediate dose is performed prior to administering thefull dose (e.g., 24 or 48 mg), as described herein. CRS can beclassified in accordance with standard practice (e.g. as outlined in Leeet al., Biol Blood Marrow Transplant 2019; 25:625-38, which isincorporated herein by reference). CRS may include excessive release ofcytokines, for example of proinflammatory cytokines, e.g., IL-6,TNF-alpha, or IL-8, that may result in adverse effects like fever,nausea, vomiting and chills. Thus, despite the unique anti-tumoractivity of bispecific antibodies such as epcoritamab, theirimmunological mode of action may trigger unwanted “side” effects, i.e.,the induction of unwanted inflammatory reactions. Hence, patients may befurther subjected to a concomitant treatment, prophylaxis, and/orpremedication with, e.g., analgesics, antipyretics, and/oranti-inflammatory drugs to mitigate possible CRS symptoms.

Accordingly, in one embodiment, human subjects in the methods describedherein are treated with prophylaxis for CRS. In preferred embodiments,the prophylaxis includes the administration of a corticosteroid to thesubject. In one embodiment, the prophylaxis (e.g. corticosteroid) isadministered on the same day as the bispecific antibody. The prophylaxis(e.g. corticosteroid) can also be administered on the subsequent days aswell. In some embodiments, the prophylaxis (e.g. corticosteroid) isfurther administered on subsequent days 2, 3, and 4. It is understoodthat days 2, 3 and 4 when relating to further medication, such asprophylaxis, is relative to the administration of the bispecificantibody which is administered on day 1. For example, when in a cyclethe antibody is administered on day 15, and prophylaxis is alsoadministered, the prophylaxis corresponding to days 2, 3 and 4 are days16, 17, and 18 of the cycle. In some embodiments, the prophylaxis isadministered on the day when the bispecific antibody is administered andon subsequent days 2-4. When said prophylaxis is administered on thesame day as the bispecific antibody, the prophylaxis is preferablyadministered 30-120 minutes prior to said administration of thebispecific antibody. The corticosteroid for use in CRS prophylaxis forthe methods described herein is preferably prednisone, as it is acomponent of the R-CHOP regimen. Thus, in preferred embodiments, thecorticosteroid is prednisone. In some embodiments, prednisone isadministered at an intravenous dose of 100 mg, or an equivalent thereof,including an oral dose. Exemplary corticosteroid equivalents ofprednisolone, along with dosage equivalents, which can be used for CRSprophylaxis are shown in Table 5.

With regard to CRS prophylaxis when the bispecific antibody (e.g.,epcoritamab) is administered on days when R-CHOP is also administered(e.g., day 1 of each 21-day cycle), it is understood that the R-CHOPregimen already provides the corticosteroid component for the CRSprophylaxis (i.e., prednisone or equivalent), as well as the subsequentadministration of corticosteroids in CRS prophylaxis for, e.g.,subsequent days 2, 3, and 4. If, however, the bispecific antibody is notadministered within about 30-120 minutes of administration of theprednisone component of R-CHOP, then, in some embodiments, an additionaldose of corticosteroid for CRS prophylaxis may be administered on thatday. On subsequent days, however, e.g., days 2, 3, and 4 after day 1when R-CHOP and the bispecific antibody were administered, only one doseof prednisone is administered (i.e., the dose serves as both CRSprophylaxis for the bispecific antibody and a component of the R-CHOPregimen). On days when the bispecific antibody is administered withoutR-CHOP (e.g., days 8 and 15 of the 21-day cycles), prednisone or anequivalent is administered as CRS prophylaxis, e.g., together withpremedication (e.g., antihistamine/antipyretic), as described below.

In one embodiment, when prednisone is administered as a part of theR-CHOP regimen on days 1-5 of a 21-day cycle (e.g., cycle 1), and thebispecific antibody is administered on day 1 of that cycle, noadditional corticosteroid is administered for CRS prophylaxis, providedthat the prednisone component of R-CHOP is administered about 30-120minutes before the bispecific antibody is administered (i.e., no doubledosing of the corticosteroid is performed). In some embodiments, whenprednisone is administered as a part of the R-CHOP regimen on days 1-5of a 21-day cycle (e.g., cycle 1), and the bispecific antibody isadministered on day 1 of that cycle, a further corticosteroid (e.g.,prednisone 100 mg or equivalent thereof) is administered as CRSprophylaxis before the bispecific antibody is administered if theprednisone component of R-CHOP is administered more than 120 minutesbefore the bispecific antibody is administered. In some embodiments, ifR-CHOP is withheld on day 1 of a 21-day cycle, and thus the prednisonecomponent of the R-CHOP regimen is not administered to the subject onthe same day as the bispecific antibody, then the subject isadministered a corticosteroid such as prednisone or its equivalent forCRS prophylaxis.

Furthermore, in some embodiments, human subjects in the methodsdescribed herein are treated with premedication to reduce reactions toinjections. In one embodiment, the premedication includes theadministration of antihistamines. In some embodiments, the premedicationincludes the administration of antipyretics. In a further embodiment,the premedication includes systemic administration of antihistamines andantipyretics.

An exemplary antihistamine suitable for use in premedication isdiphenhydramine. Thus, in one embodiment, the antihistamine for use inpremedication is diphenhydramine. In one embodiment, diphenhydramine isadministered at an intravenous or oral dose 50 mg, or an equivalentthereof. An exemplary antipyretic suitable for use in premedication isacetaminophen. Thus, in one embodiment, the antipyretic for use inpremedication is acetaminophen. In one embodiment, acetaminophen isadministered at an oral dose of 650-1000 mg, or equivalent thereof. Insome embodiments, the premedication is administered on the same day asthe bispecific antibody, for example, prior to the injection with thebispecific antibody, e.g., 30-120 minutes prior to administration of thebispecific antibody. In some embodiments, the antihistamine (e.g.diphenhydramine) is administered on the same day as the bispecificantibody, for example, prior to the injection with the bispecificantibody, e.g., 30-120 minutes prior to administration of the bispecificantibody in an intravenous or oral dose of (or about) 50 mg. In someembodiments, the antipyretic (e.g. acetaminophen) is administered on thesame day as the bispecific antibody, for example, prior to the injectionwith the bispecific antibody, e.g., 30-120 minutes prior toadministration of the bispecific antibody in an oral dose of (or about)650-1000 mg. In some embodiments, the antihistamine (e.g.diphenhydramine) and the antipyretic (e.g. acetaminophen) areadministered on the same day as the bispecific antibody, for example,prior to the injection with the bispecific antibody, e.g., 30-120minutes prior to administration of the bispecific antibody in anintravenous or oral dose of (or about) 50 mg and an oral dose of (orabout) 650-1000 mg, respectively.

Premedication and/or prophylaxis for CRS can be administered at least inthe initial phase of the treatment. In some embodiments, premedicationand/or prophylaxis is administered during the first four administrationsof the bispecific antibody. For example, the prophylaxis and/orpremedication can be administered as described herein, during the threeadministrations of the bispecific antibody in the first 21-day cycle andfirst administration of the bispecific antibody of the second 21-daycycle. In one embodiment, on day 1 of the first and second 21-daycycles, the prednisone component of the R-CHOP regimen serves as thecorticosteroid for prophylaxis of CRS.

Usually, risk of reactions during the initial treatment subsides after afew administrations, e.g., after the first four administrations (threeadministrations in first cycle and first administration in secondcycle). Hence, when the human subject does not experience CRS with thefourth administration, prophylaxis for CRS may be stopped. Thus, in someembodiments, the premedication and/or prophylaxis is administered incycle 1 and start of cycle 2 of the 21-day cycles. In some embodiments,the premedication is administered in cycle 1 and start of cycle 2 of the21-day cycles. In some embodiments, the prophylaxis is administered incycle 1 and start of cycle 2 of the 21-day cycles. However, CRSprophylaxis may continue, particularly when the human subjectexperiences a CRS greater than grade 1. Likewise, premedication may alsooptionally continue. CRS grading can be performed as described in Tables6 and 7.

In a further embodiment, in the methods described herein, theprophylaxis is administered during the second and third administrationsof the bispecific antibody during cycle 2 of the 21-day cycles when thesubject experiences CRS greater than grade 1 after the firstadministration of the bispecific antibody in cycle 2 of the 21-daycycles i.e. the prophylaxis for CRS is continued in the second 21-daycycle when the human subject experiences CRS greater than grade 1 afterthe first (i.e. fourth administration) administration of the bispecificantibody in cycle 2 (i.e., day 1 of cycle 2 of the 21-day cycles).Furthermore, the prophylaxis can be continued during a subsequent cycle,when in the last administration of the bispecific antibody of theprevious cycle, the human subject experiences CRS greater than grade 1.Thus, in some embodiments, the prophylaxis is continued in a subsequentcycle, when in the last administration of the bispecific antibody of theprevious cycle, the subject experiences CRS greater than grade 1. Anypremedication may be optionally administered during the second cycle(i.e. cycle 2). Further premedication may be optionally administeredduring subsequent cycles as well.

In one embodiment, premedication and prophylaxis for CRS isadministered, including an antihistamine such as diphenhydramine (e.g.,at an intravenous or oral dose 50 mg, or an equivalent thereof), anantipyretic such as acetaminophen (e.g., at an oral dose of 650-1000 mg,or an equivalent thereof), and a corticosteroid such as prednisone(e.g., at an intravenous dose of 100 mg, or an equivalent thereof). Insome embodiments, the premedication and prophylaxis is administered30-120 minutes prior to administration of the bispecific antibody. Onsubsequent days 2, 3, and 4, further prophylaxis is administeredcomprising the systemic administration of a corticosteroid such asprednisone (e.g., at an intravenous dose of 100 mg, or an equivalentthereof). In some embodiments, the premedication and prophylaxisschedule preferably is administered during the first fouradministrations of the bispecific antibody, e.g., during the first21-day cycle and start of the second 21-day cycle of bispecific antibodyadministration described herein. Furthermore, subsequent cycles, in caseof, e.g., CRS greater than grade 1 occurring during the lastadministration of the prior cycle, can include the same administrationschedule, wherein the premedication as part of the administrationschedule is optional. As discussed above, however, the corticosteroidcomponent of the CRS prophylaxis may not be administered to the subjectduring the first administration of the bispecific antibody, on day 1 andsubsequent days 2-4, of each 21-day cycle if prednisone is administeredas part of the R-CHOP regimen.

During the treatment of a human subject with DLBCL using the doses andtreatment regimens described herein, CRS can be well managed while atthe same time effectively controlling and/or treating the DLBCL. Asdescribed in the Examples, subjects treated with the methods describedherein may experience manageable CRS. In some cases, subjects receivingthe treatment described herein may develop CRS of grade 1 as defined inaccordance with standard practice. In other cases, subjects may developmanageable CRS of grade 2 as defined in accordance with standardpractice. Hence, subjects receiving the treatments described herein mayhave manageable CRS of grade 1 or grade 2 during as defined inaccordance with standard practice. In accordance with standardclassification for CRS, a grade 1 CRS includes a fever to at least 38°C., no hypotension, no hypoxia, and a grade 2 CRS includes a fever to atleast 38° C. plus hypotension, not requiring vasopressors and/or hypoxiarequiring oxygen by low flow nasal cannula or blow by. Such manageableCRS can occur during cycle 1. Human subjects receiving the treatmentsdescribed herein may also have CRS greater than grade 2 during thetreatments as defined in accordance with standard practice. Hence, humansubjects receiving the treatments described herein may also have CRS ofgrade 3 during said treatments as defined in accordance with standardpractice. Such manageable CRS may further occur during cycle 1 andsubsequent cycles.

Human subjects treated according to the methods described herein mayalso experience pyrexia, fatigue, and injection site reactions. They mayalso experience neurotoxicity, partial seizures, agraphia related toCRS, or confusional state related to CRS.

As mentioned above, subjects may develop CRS during treatment with themethods described herein, despite having received CRS prophylaxis. CRSgrading criteria are described in Tables 6 and 7.

In a preferred embodiment, subjects who develop Grade 1 CRS are treatedwith antibiotics if they present with infection i.e. the subject isadministered antibiotics if the subject develops Grade 1 CRS. In someembodiments, the antibiotics are continued until neutropenia, ifpresent, resolves. In some embodiments, subjects with Grade 1 CRS whoexhibit constitutional symptoms are treated with NSAIDs.

In one embodiments, subjects who develop Grade 2 CRS are treated withintravenous fluid boluses and/or supplemental oxygen. In one embodiment,subjects who develop Grade 2 CRS are treated with a vasopressor (e.g.,norepinephrine). In one embodiment, subjects with Grade 2 CRS withcomorbidities are treated with tocilizumab (a humanized antibody againstIL-6 receptor, commercially available as, e.g., ACTEMRA®). In oneembodiment, subjects with Grade 2 CRS are treated with tocilizumab and asteroid. In one embodiment, the steroid is dexamethasone. In oneembodiment, the steroid is methylprednisolone. In a further embodiment,a subject who presents with concurrent ICANS is administereddexamethasone. In yet a further embodiment, if the subject does not showimprovement in CRS symptoms within, e.g., 6 hours, or if the subjectstarts to deteriorate after initial improvement, then a second dose oftocilizumab is administered together with a dose of corticosteroids. Insome embodiments, if the subject is refractory to tocilizumab afterthree administrations, then additional cytokine therapy, e.g., ananti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g.,anakinra) is administered to the subject.

In one embodiment, subjects who develop Grade 3 CRS are treated withvasopressor (e.g., norepinephrine) support and/or supplemental oxygen.In some embodiments, subjects with Grade 3 CRS are treated withtocilizumab. In one embodiment, subjects with Grade 3 CRS are treatedwith tocilizumab in combination with steroids (e.g., dexamethasone orits equivalent of methylprednisolone). In some embodiments, a subjectwho presents with concurrent ICANS is administered dexamethasone. In afurther embodiment, if the subject is refractory to tocilizumab afterthree administrations, then additional cytokine therapy, e.g., ananti-IL-6 antibody (e.g., siltuximab) or an IL-1R antagonist (e.g.,anakinra) is administered to the subject.

In one embodiment, subjects who develop Grade 4 CRS are treated withvasopressor (e.g., norepinephrine) support and/or supplemental oxygen(e.g., via positive pressure ventilation, such as CPAP, BiPAP,intubation, or mechanical ventilation). In one embodiment, subjects whodevelop Grade 4 CRS are administered at least two vasopressors. In oneembodiment, subjects who develop Grade 4 CRS are administeredtocilizumab and a steroid (e.g., dexamethasone or its equivalent ofmethylprednisolone). In a further embodiment, a subject who presentswith concurrent ICANS is administered dexamethasone. If the subject isrefractory to tocilizumab after three administrations, then additionalcytokine therapy, e.g., an anti-IL-6 antibody (e.g., siltuximab) or anIL-1R antagonist (e.g., anakinra) is administered to the subject. Insome embodiments, tocilizumab is switched to an IL-6 antibody (e.g.,siltuximab) if the subject is refractory to tocilizumab. In someembodiments, tocilizumab is switched to an IL-1R antagonist (e.g.,anakinra) if the subject is refractory to tocilizumab.

In some embodiments, the human subject receives prophylactic treatmentfor tumor lysis syndrome (TLS) i.e. the subject is treated withprophylaxis for TLS. Classification and grading of tumor lysis syndromecan be performed using methods known in the art, for example, asdescribed in Howard et al. N Engl J Med 2011; 364:1844-54, and Coiffieret al., J Clin Oncol 2008; 26:2767-78. In some embodiments, prophylaxis(prophylactic treatment) of TLS comprises administering one or more uricacid reducing agents prior to administering the bispecific antibody.Exemplary uric acid reducing agents include rasburicase and allopurinol.Accordingly, in one embodiment, the prophylactic treatment of TLScomprises administering rasburicase. In one embodiment, the prophylactictreatment of TLS comprises administering allopurinol. In one embodiment,the prophylactic treatment of TLS comprises administering allopurinoland allopurinol prior to administering the bispecific antibody. In someembodiments, when the subject shows signs of TLS, supportive therapy,such as rasburicase, may be used.

Subjects being administered rituximab according to the methods describedherein can be treated with supportive therapies. In one embodiment,supportive therapies include, but are not limited to, (a) premedicationwith acetaminophen (e.g., 650 mg orally), diphenhydramine (e.g., 50-100mg intravenously or orally), and steroids, for example, 30-60 minutesprior to starting each rituximab infusion, (b) prophylactic treatmentfor Pneumocystis carinii pneumonia, (c) CNS prophylaxis according tostandard local practice (e.g., methotrexate), (d) low-dose aspirin(e.g., 70-100 mg daily) or another prophylactic antithrombotic treatmentfor subjects without a prior history of deep vein thrombosis (DVT) orpulmonary embolism (PE) within 5 years of initiating treatment andconsidered to be at standard risk for thrombosis, and/or (e)anticoagulation therapy for subjects with a prior medical history of DVTor PE within 5 years of initiating treatment.

In one embodiment, the bispecific antibody used in the methods describedherein is administered subcutaneously, and thus is formulated in apharmaceutical composition such that it is compatible with subcutaneous(s.c.) administration, i.e., having a formulation and/or concentrationthat allows pharmaceutical acceptable s.c. administration at the dosesdescribed herein. In some embodiments, subcutaneous administration iscarried out by injection. For example, formulations for DuoBody CD3xCD20that are compatible with subcutaneous formulation and can be used in themethods described herein have been described previously (see, e.g.,WO2019155008, which is incorporated herein by reference). In someembodiments, the bispecific antibody may be formulated using sodiumacetate trihydrate, acetic acid, sodium hydroxide, sorbitol, polysorbate80, and water for injection, and have a pH of 5.5 or about 5.5. In someembodiments, the bispecific antibody is provided as a 5 mg/mL or 60mg/mL concentrate. In other embodiments, the desired dose of thebispecific antibody is reconstituted to a volume of about 1 mL forsubcutaneous injection.

In one embodiment, a suitable pharmaceutical composition for thebispecific antibody can comprise the bispecific antibody, 20-40 mMacetate, 140-160 mM sorbitol, and a surfactant, such as polysorbate 80,and having a pH of 5.3-5.6. In some embodiments, the pharmaceuticalformulation may comprise an antibody concentration in the range of 5-100mg/mL, e.g., 48 or 60 mg/mL of the bispecific antibody, 30 mM acetate,150 mM sorbitol, 0.04% w/v polysorbate 80, and have a pH of 5.5. Such aformulation may be diluted with, e.g., the formulation buffer to allowproper dosing and subcutaneous administration.

The volume of the pharmaceutical composition is appropriately selectedto allow for subcutaneous administration of the antibody. For example,the volume to be administered is in the range of about 0.3 mL to about 3mL, such as from 0.3 mL to 3 mL. The volume to be administered can be0.5 mL, 0.8 mL, 1 mL, 1.2 mL, 1.5 ml, 1.7 mL, 2 mL, or 2.5 mL, or about0.5 mL, about 0.8 mL, about 1 mL, about 1.2 mL, about 1.5 ml, about 1.7mL, about 2 mL, or about 2.5 mL. Accordingly, in one embodiment, thevolume to be administered is 0.5 mL or about 0.5 mL. In someembodiments, the volume to be administered is 0.8 mL or about 0.8 mL. Insome embodiments, the volume to be administered is 1 mL or about 1 mL.In some embodiments, the volume to be administered is 1.2 mL or about1.2 mL. In some embodiments, the volume to be administered is 1.5 mL orabout 1.5 mL. In some embodiments, the volume to be administered is 1.7mL or about 1.7 mL. In some embodiments, the volume to be administeredis 2 mL or about 2 mL. In some embodiments, the volume to beadministered is 2.5 mL or about 2.5 mL.

In one embodiment, rituximab is formulated in a pharmaceuticalcomposition comprising pharmaceutically-acceptable excipients foradministration (e.g., intravenous administration) in accordance withlocal standard-of-care practice, e.g., as specified by local guidelinesor local product labels. For example, in some embodiments, rituximab isprovided as a sterile, clear, colorless, preservative-free liquidconcentrate for intravenous administration. In one embodiment, rituximabis supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500mg/50 mL single-use vials. In some embodiments, rituximab is formulatedin polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL),sodium chloride (9 mg/mL), and water, at a pH of 6.5, for injection.

In one embodiment, cyclophosphamide, doxorubicin, vincristine, andprednisone are formulated in a pharmaceutical composition comprisingpharmaceutically-acceptable excipients for administration (e.g.,intravenous administration) in accordance with local standard-of-carepractice, e.g., as specified by local guidelines or local productlabels, or as directed by the manufacturer. In some embodiments,cyclophosphamide, doxorubicin, vincristine, and prednisone are dilutedfrom a stock solution, or reconstituted if in lyophilized form,according to, e.g., instructions in the product label (e.g., with 0.9%saline solution). In some embodiments, prednisone is formulated in apharmaceutical composition for oral administration.

In one embodiment, the bispecific antibody used in the methods describedherein comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a        variable heavy chain (VH) region and a variable light chain (VL)        region, wherein the VH region comprises the CDR1, CDR2 and CDR3        sequences within the amino acid sequence of SEQ ID NO: 6, and        the VL region comprises the CDR1, CDR2 and CDR3 sequences within        the amino acid sequence of SEQ ID NO: 7; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region and a        VL region, wherein the VH region comprises the CDR1, CDR2 and        CDR3 sequences within the amino acid sequence of SEQ ID NO: 13,        and the VL region comprises the CDR1, CDR2 and CDR3 sequences        within the amino acid sequence SEQ ID NO: 14.

CDR1, CDR2 and CDR3 regions can be identified from variable heavy andlight chain regions using methods known in the art. The CDR regions fromsaid variable heavy and light chain regions can be annotated accordingto IMGT (see Lefranc et al., Nucleic Acids Research 1999; 27:209-12,1999] and Brochet. Nucl Acids Res 2008; 36:W503-8).

In one embodiment, the bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises VHCDR1,        VHCDR2 and VHCDR3 the amino acid sequences set forth in SEQ ID        NOs: 1, 2, and 3, respectively, and VLCDR1, VLCDR2, and VLCDR3        comprising the amino acid sequences set forth in SEQ ID NO: 4,        the sequence GTN, and SEQ ID NO: 5, respectively; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises VHCDR1, VHCDR2,        and VHCDR3 comprising the amino acid sequences set forth in SEQ        ID NOs: 8, 9, and 10, respectively, and VLCDR1, VLCDR2, and        VLCDR3 comprising the amino acid sequences set forth in SEQ ID        NO: 11, the sequence DAS, and SEQ ID NO: 12, respectively.

In one embodiment, the bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a VH        region comprising the amino acid sequence of SEQ ID NO: 6, and a        VL region comprising the amino acid sequence of SEQ ID NO: 7;        and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region        comprising the amino acid sequence of SEQ ID NO: 13, and a VL        region comprising the amino acid sequence of SEQ ID NO: 14.

In one embodiment, the bispecific antibody is a full-length antibody. Insome embodiments, the bispecific antibody have an inert Fc region. Insome embodiments, the bispecific antibody is a full-length antibody andhave an inert Fc region. In some embodiments, the first binding arm forCD3 is derived from a humanized antibody, e.g., from a full-lengthIgG1,λ (lambda) antibody such as H1L1 described in WO2015001085, whichis incorporated herein by reference, and/or the second binding arm forCD20 is derived from a human antibody, e.g., from a full-length IgG1,κ(kappa) antibody such as clone 7D8 as described in WO2004035607, whichis incorporated herein by reference. The bispecific antibody may beproduced from two half molecule antibodies, wherein each of the two halfmolecule antibodies comprising, e.g., the respective first and secondbinding arms set forth in SEQ ID NOs: 24 and 25, and SEQ ID NOs: 26 and27. The half-antibodies may be produced in CHO cells and the bispecificantibodies generated by, e.g., Fab-arm exchange. In one embodiment, thebispecific antibody is a functional variant of DuoBody CD3xCD20.

Accordingly, in some embodiments, the bispecific antibody comprises (i)a first binding arm comprising a first antigen-binding region whichbinds to human CD3ε (epsilon) and comprises a VH region comprising anamino acid sequence which is at least 85%, 90%, 95%, 96%, 97%, 98%, or99% identical to SEQ ID NO: 6 or a VH region comprising the amino acidsequence of SEQ ID NO: 6, but with 1, 2, or 3 mutations (e.g., aminoacid substitutions), and a VL region comprising an amino acid sequencewhich is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQID NO: 7 or a VL region comprising the amino acid sequence of SEQ ID NO:7, but with 1, 2, or 3 mutations (e.g., amino acid substitutions); and

-   -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region        comprising an amino acid sequence which is at least 85%, 90%,        95%, 98%, or 99% identical to SEQ ID NO: 13 or a VH region        comprising the amino acid sequence of SEQ ID NO: 13, but with 1,        2, or 3 mutations (e.g., amino acid substitutions), and a VL        region comprising an amino acid sequence which is at least 85%,        90%, 95%, 98%, or 99% identical to SEQ ID NO: 14 or a VL region        comprising the amino acid sequence of SEQ ID NO: 14, but with 1,        2, or 3 mutations (e.g., amino acid substitutions).

In one embodiment, the bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a heavy        chain comprising the amino acid sequence of SEQ ID NO: 24, and a        light chain comprising the amino acid sequence of SEQ ID NO: 25;        and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region        comprising the amino acid sequence of SEQ ID NO: 26, and a VL        region comprising the amino acid sequence of SEQ ID NO: 27.

In some embodiments, the bispecific antibody comprises (i) a firstbinding arm comprising a first antigen-binding region which binds tohuman CD3ε (epsilon) and comprises a heavy chain comprising an aminoacid sequence which is at least 85%, 90%, 95%, 98%, or 99% identical toSEQ ID NO: 24 or a heavy chain comprising the amino acid sequence of SEQID NO: 24, but with 1, 2, or 3 mutations (e.g., amino acidsubstitutions), and a light chain comprising an amino acid sequencewhich is at least 85%, 90%, 95%, 98%, or 99% identical to SEQ ID NO: 25or a light chain region comprising the amino acid sequence of SEQ ID NO:25, but with 1, 2, or 3 mutations (e.g., amino acid substitutions); and

-   -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a heavy chain        comprising an amino acid sequence which is at least 85%, 90%,        95%, 98%, or 99% identical to SEQ ID NO: 26 or a heavy chain        comprising the amino acid sequence of SEQ ID NO: 26, but with 1,        2, or 3 mutations (e.g., amino acid substitutions), and a light        chain comprising an amino acid sequence which is at least 85%,        90%, 95%, 98%, or 99% identical to SEQ ID NO: 27 or a light        chain region comprising the amino acid sequence of SEQ ID NO:        27, but with 1, 2, or 3 mutations (e.g., amino acid        substitutions).

Various constant regions or variants thereof may be used in thebispecific antibody. In one embodiment, the antibody comprises an IgGconstant region, such as a human IgG1 constant region, e.g., a humanIgG1 constant region as defined in SEQ ID NO: 15, or any other suitableIgG1 allotype. In one embodiment, the bispecific antibody is afull-length antibody with a human IgG1 constant region. In oneembodiment, the first binding arm of the bispecific antibody is derivedfrom a humanized antibody, preferably from a full-length IgG1,λ (lambda)antibody. In one embodiment, the first binding arm of the bispecificantibody is derived from a humanized antibody, e.g., from a full-lengthIgG1,λ (lambda) antibody, and thus comprises a λ light chain constantregion. In some embodiments, the first binding arm comprises a λ lightchain constant region as defined in SEQ ID NO: 22. In one embodiment,the second binding arm of the bispecific antibody is derived from ahuman antibody, preferably from a full-length IgG1,κ (kappa) antibody.In one embodiment the second binding arm of the bispecific antibody isderived from a human antibody, preferably from a full-length IgG1,κ(kappa) antibody, and thus may comprise a κ light chain constant region.In some embodiments, the second binding arm comprises a κ light chainconstant region as defined in SEQ ID NO: 23. In a preferred embodiment,the first binding arm comprises a λ light chain constant region asdefined in SEQ ID NO: 22 and the second binding arm comprises a κ lightchain constant region as defined in SEQ ID NO: 23.

It is understood that the constant region portion of the bispecificantibody may comprise modifications that allow for efficientformation/production of bispecific antibodies and/or provide for aninert Fc region. Such modifications are well known in the art.

Different formats of bispecific antibodies are known in the art(reviewed by Kontermann, Drug Discov Today 2015; 20:838-47; MAbs, 2012;4:182-97). Thus, the bispecific antibody used in the methods and usesdescribed herein are not limited to any particular bispecific format ormethod of producing it. For example, bispecific antibodies may include,but are not limited to, bispecific antibodies with complementary CH3domains to force heterodimerization, Knobs-into-Holes molecules(Genentech, WO9850431), CrossMAbs (Roche, WO2011117329), orelectrostatically-matched molecules (Amgen, EP1870459 and WO2009089004;Chugai, US201000155133; Oncomed, WO2010129304).

Preferably, the bispecific antibody comprises an Fc-region comprising afirst heavy chain with a first Fc sequence comprising a first CH3region, and a second heavy chain with a second Fc sequence comprising asecond CH3 region, wherein the sequences of the first and second CH3regions are different and are such that the heterodimeric interactionbetween said first and second CH3 regions is stronger than each of thehomodimeric interactions of said first and second CH3 regions. Furtherdetails on these interactions and how they can be achieved are providedin e.g. WO2011131746 and WO2013060867 (Genmab), which are herebyincorporated by reference. In one embodiment, the bispecific antibodycomprises in the first heavy chain (i) the amino acid L in the positioncorresponding to F405 in the human IgG1 heavy chain constant region ofSEQ ID NO: 15, and comprises in the second heavy chain the amino acid Rin the position corresponding to K409 in the human IgG1 heavy chainconstant region of SEQ ID NO: 15, or vice versa.

Bispecific antibodies may comprise modifications in the Fc region torender the Fc region inert, or non-activating. Thus, in the bispecificantibodies disclosed herein, one or both heavy chains may be modified sothat the antibody induces Fc-mediated effector function to a lesserextent relative to the bispecific antibody which does not have themodification. Fc-mediated effector function may be measured bydetermining Fc-mediated CD69 expression on T cells (i.e. CD69 expressionas a result of CD3 antibody-mediated, Fcγ receptor-dependent CD3crosslinking), by binding to Fcγ receptors, by binding to C1q, or byinduction of Fc-mediated cross-linking of FcγRs. In particular, theheavy chain constant region sequence may be modified so that Fc-mediatedCD69 expression is reduced by at least 50%, at least 60%, at least 70%,at least 80%, at least 90%, at least 99% or 100% when compared to awild-type (unmodified) antibody, wherein said Fc-mediated CD69expression is determined in a PBMC-based functional assay, e.g. asdescribed in Example 3 of WO2015001085. Modifications of the heavy andlight chain constant region sequences may also result in reduced bindingof C1q to said antibody. As compared to an unmodified antibody, thereduction may be by at least 70%, at least 80%, at least 90%, at least95%, at least 97%, or 100%, and C1q binding may be determined, e.g., byELISA. Further, the Fc region which may be modified so that the antibodymediates reduced Fc-mediated T-cell proliferation compared to anunmodified antibody by at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 99% or 100%, wherein said T-cellproliferation is measured in a PBMC-based functional assay. Examples ofamino acid positions that may be modified, e.g., in an IgG1 isotypeantibody, include positions L234 and L235. Thus, in one embodiment, thebispecific antibody may comprises a first heavy chain and a second heavychain, and wherein in both the first heavy chain and the second heavychain, the amino acid residues at the positions corresponding topositions L234 and L235 in a human IgG1 heavy chain according to Eunumbering are F and E, respectively. In addition, a D265A amino acidsubstitution can decrease binding to all Fcγ receptors and prevent ADCC(Shields et al., JBC 2001; 276:6591-604). Therefore, the bispecificantibody may comprise a first heavy chain and a second heavy chain,wherein in both the first heavy chain and the second heavy chain, theamino acid residue at the position corresponding to position D265 in ahuman IgG1 heavy chain according to Eu numbering is A.

In one embodiment, in the first heavy chain and second heavy chain ofthe bispecific antibody, the amino acids in the positions correspondingto positions L234, L235, and D265 in a human IgG1 heavy chain, are F, E,and A, respectively. An antibody having these amino acids at thesepositions is an example of an antibody having an inert Fc region, or anon-activating Fc region. In one embodiment, the bispecific antibodycomprises a first heavy chain and a second heavy chain, wherein in boththe first and second heavy chains, the amino acids in the positionscorresponding to positions L234, L235, and D265 in the human IgG1 heavychain constant region of SEQ ID NO: 15 are F, E, and A, respectively. Inone embodiment, the bispecific antibody comprises a first heavy chainand a second heavy chain, wherein in the first heavy chain, the aminoacid in the position corresponding to F405 in the human IgG1 heavy chainconstant region of SEQ ID NO: 15 is L, and wherein in the second heavychain, the amino acid in the position corresponding to K409 in the humanIgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.In a preferred embodiment, the bispecific antibody comprises a firstheavy chain and a second heavy chain, wherein (i) in both the first andsecond heavy chains, the amino acids in the positions corresponding topositions L234, L235, and D265 in the human IgG1 heavy chain constantregion of SEQ ID NO: 15 are F, E, and A, respectively, and (ii) in thefirst heavy chain, the amino acid in the position corresponding to F405in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, andwherein in the second heavy chain, the amino acid in the positioncorresponding to K409 in the human IgG1 heavy chain constant region ofSEQ ID NO: 15 is R, or vice versa.

With regard to the bispecific antibodies described herein, those whichhave the combination of three amino acid substitutions L234F, L235E andD265A and in addition the K409R or the F405L mutation, as describedabove, may be referred to with the suffix “FEAR” or “FEAL”,respectively.

An amino acid sequence of a wild type IgG1 heavy chain constant regionmay be identified herein as SEQ ID NO: 15. Consistent with theembodiments disclosed above, the bispecific antibody may comprise anIgG1 heavy chain constant region carrying the F405L substitution and mayhave the amino acid sequence set forth in SEQ ID NO: 17 and/or an IgG1heavy chain constant region carrying the K409R substitution and may havethe amino acid sequence set forth in SEQ ID NO: 18, and have furthersubstitutions that render the Fc region inert or non-activating. Hence,in one embodiment, the bispecific antibody comprises a combination ofIgG1 heavy chain constant regions, with the amino acid sequence of oneof the IgG1 heavy chain constant regions carrying the L234F, L235E,D265A and F405L substitutions (e.g., as set forth in SEQ ID NO: 19) andthe amino acid sequence of the other IgG1 heavy chain constant regioncarrying the L234F, L235E, D265A and K409R substitutions (e.g., as setforth in SEQ ID NO: 20). Thus, in one embodiment, the bispecificantibody comprises heavy chain constant regions comprising the aminoacid sequences of SEQ ID NOs: 19 and 20.

In preferred embodiments, the bispecific antibody used in the methodsand uses described herein comprises a first binding arm comprising aheavy chain and a light chain as defined in SEQ ID NOs: 24 and 25,respectively, and a second binding arm comprising a heavy chain and alight chain as defined in SEQ ID NOs: 26 and 27, respectively. Such anantibody is referred to herein as DuoBody CD3xCD20. Also, variants ofsuch antibodies are contemplated use in the methods and uses asdescribed herein. In some embodiment, the bispecific antibody comprisinga heavy chain and a light chain consisting of the amino acid sequencesset forth in SEQ ID NOs: 24 and 25, respectively, and a heavy chain anda light chain consisting of the amino acid sequences set forth in SEQ IDNOs: 26 and 27, respectively. In some embodiments, the bispecificantibody is epcoritamab (CAS 2134641-34-0), or a biosimilar thereof.

Kits

Also provided herein are kits which include a pharmaceutical compositioncontaining a bispecific antibody which binds to CD3 and CD20 inaccordance with the invention, such as DuoBody CD3xCD20 or epcoritamab,and a pharmaceutically-acceptable carrier, in a therapeuticallyeffective amount adapted for use in the methods described herein. Thekits may also include a pharmaceutical composition containing rituximab(e.g., for intravenous administration), cyclophosphamide (e.g., forintravenous administration), doxorubicin (e.g., for intravenousadministration), vincristine (e.g., for intravenous administration),and/or prednisone (e.g., for intravenous or oral administration). Thekits optionally also can include instructions, e.g., comprisingadministration schedules, to allow a practitioner (e.g., a physician,nurse, or patient) to administer the composition or compositionscontained therein to a patient with DLBCL. The kit also can include asyringe or syringes.

Optionally, the kits include multiple packages of the single-dosepharmaceutical compositions each containing an effective amount of thebispecific antibody for a single administration in accordance with themethods described herein. They may also include multiple packages ofsingle dose pharmaceutical compositions containing a dose of rituximab,cyclophosphamide, doxorubicin, vincristine, and/or prednisone inaccordance with a standard of care regimen. Instruments or devicesnecessary for administering the pharmaceutical composition(s) also maybe included in the kits.

FURTHER EMBODIMENTS

1. A bispecific antibody comprising:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a        variable heavy chain (VH) region and a variable light chain (VL)        region, wherein the VH region comprises the CDR1, CDR2 and CDR3        sequences that are in the VH region sequence of SEQ ID NO: 6,        and the VL region comprises the CDR1, CDR2 and CDR3 sequences        that are in the VL region sequence of SEQ ID NO: 7; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region and a        VL region, wherein the VH region comprises the CDR1, CDR2 and        CDR3 sequences that are in the VH region sequence of SEQ ID NO:        13, and the VL region comprises the CDR1, CDR2 and CDR3        sequences that are in the VL region sequence of SEQ ID NO: 14;    -   for use in the treatment of diffuse large B-cell lymphoma        (DLBCL) in a human subject, wherein the treatment comprises        administering the bispecific antibody and an effective amount of        rituximab, cyclophosphamide, doxorubicin, vincristine, and        prednisone to the human subject, wherein the bispecific antibody        is administered at a dose of 24 mg or 48 mg, and wherein the        bispecific antibody, rituximab, cyclophosphamide, doxorubicin,        vincristine, and prednisone are administered in 21-day cycles.

2. The bispecific antibody of embodiment 1, wherein the bispecificantibody is administered at a dose of 24 mg.

3. The bispecific antibody of embodiment 1, wherein the bispecificantibody is administered at a dose of 48 mg.

4. The bispecific antibody of any one of embodiments 1-3, wherein thebispecific antibody is administered once every week (weeklyadministration).

5. The bispecific antibody of embodiment 4, wherein the weeklyadministration of 24 mg or 48 mg is performed for three and one-third21-day cycles.

6. The bispecific antibody of embodiment 4 or 5, wherein after theweekly administration, the bispecific antibody is administered onceevery three weeks.

7. The bispecific antibody of embodiment 6, wherein the administrationonce every three weeks is performed for two or four 21-day cycles.

8. The bispecific antibody of embodiment 7, wherein after theadministration once every three weeks, the bispecific antibody isadministered once every four weeks in 28-day cycles.

9. The bispecific antibody of embodiment 8, wherein the administrationonce every four weeks is performed for up to one year total duration oftreatment with the bispecific antibody.

10. The bispecific antibody of any one of embodiments 4-9, wherein priorto the weekly administration of 24 mg or 48 mg, a priming dose of thebispecific antibody is administered in cycle 1 of the 21-day cycles.

11. The bispecific antibody of embodiment 10, wherein the priming doseis administered two weeks prior to administering the first weekly doseof 24 mg or 48 mg.

12. The bispecific antibody of embodiment 10 or 11, wherein the primingdose is 0.16 mg.

13. The bispecific antibody of any one of embodiments 10-12, whereinafter administering the priming dose and prior to administering thefirst weekly dose of 24 mg or 48 mg, an intermediate dose of thebispecific antibody is administered.

14. The bispecific antibody of embodiment 13, wherein the priming doseis administered on day 1 and the intermediate dose is administered onday 8 before the first weekly dose of 24 mg or 48 mg on day 15 of cycle1.

15. The bispecific antibody of embodiment 13 or 14, wherein theintermediate dose is 0.8 mg.

16. The bispecific antibody of any one of embodiments 1-15, whereinrituximab is administered once every three weeks.

17. The bispecific antibody of embodiment 16, wherein the administrationof rituximab once every three weeks is performed for six or eight 21-daycycles.

18. The bispecific antibody of any one of embodiments 1-17, whereinrituximab is administered at a dose of 375 mg/m².

19. The bispecific antibody of any one of embodiments 1-18, whereincyclophosphamide is administered once every three weeks.

20. The bispecific antibody of embodiment 19, wherein the administrationof cyclophosphamide once every three weeks is performed for six or eight21-day cycles.

21. The bispecific antibody of any one of embodiments 1-20, whereincyclophosphamide is administered at a dose of 750 mg/m².

22. The bispecific antibody of any one of embodiments 1-21, whereindoxorubicin is administered once every three weeks.

23. The bispecific antibody of embodiment 22, wherein the administrationof doxorubicin once every three weeks is performed for six or eight21-day cycles.

24. The bispecific antibody of any one of embodiments 1-23, whereindoxorubicin is administered at a dose of 50 mg/m².

25. The bispecific antibody of any one of embodiments 1-24, whereinvincristine is administered once every three weeks.

26. The bispecific antibody of embodiment 25, wherein the administrationof vincristine once every three weeks is performed for six or eight21-day cycles.

27. The bispecific antibody of any one of embodiments 1-26, whereinvincristine is administered at a dose of 1.4 mg/m².

28. The bispecific antibody of any one of embodiments 1-27, whereinprednisone is administered once a day from day 1 to day 5 of the 21-daycycles.

29. The bispecific antibody of embodiment 28, wherein prednisone isadministered for six or eight 21-day cycles.

30. The bispecific antibody of any one of embodiments 1-29, whereinprednisone is administered at a dose of 100 mg/day.

31. The bispecific antibody of any one of embodiments 1-30, whereinrituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, andthe bispecific antibody are administered on the same day (e.g., on day 1of cycles 1-6 or cycles 1-8 of the 21-day cycles).

32. The bispecific antibody of any one of embodiments 1-31, wherein thedosing schedule for rituximab, cyclophosphamide, doxorubicin,vincristine, prednisone, and the bispecific antibody is as shown inTable 2.

33. The bispecific antibody of any one of embodiments 1, 2, and 4-32,wherein administration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 24 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

34. The bispecific antibody of any one of embodiments 1 and 3-32,wherein administration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 48 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

35. The bispecific antibody of embodiment 33 or 34 wherein thebispecific antibody is administered once every four weeks in 28-daycycles on day 1 from cycle 7.

36. The bispecific antibody of any one of embodiments 1, 2, and 4-32,wherein administration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

37. The bispecific antibody of any one of embodiments 1 and 3-32,wherein administration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

38. The bispecific antibody of embodiment 36 or 37, wherein thebispecific antibody is administered once every four weeks in 28-daycycles on day 1 from cycle 9.

39. The bispecific antibody of any one of embodiments 1-38, wherein thebispecific antibody is administered subcutaneously.

40. The bispecific antibody of any one of embodiments 1-39, whereinrituximab is administered intravenously.

41. The bispecific antibody of any one of embodiments 1-40, whereincyclophosphamide is administered intravenously.

42. The bispecific antibody of any one of embodiments 1-41, whereindoxorubicin is administered intravenously.

43. The bispecific antibody of any one of embodiments 1-42, whereinvincristine is administered intravenously.

44. The bispecific antibody of any one of embodiments 1-43, whereinprednisone is administered intravenously or orally.

45. The bispecific antibody of any one of embodiments 1-44, whereinrituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, andthe bispecific antibody are administered sequentially.

46. The bispecific antibody of any one of embodiments 1-45, whereinprednisone is administered first, rituximab is administered second,cyclophosphamide is administered third, doxorubicin is administeredfourth, vincristine is administered fifth, and the bispecific antibodyis administered last if rituximab, cyclophosphamide, doxorubicin,vincristine, prednisone, and the bispecific antibody are administered onthe same day.

47. The bispecific antibody of any one of embodiments 1-46, wherein theDLBCL is double-hit or triple-hit DLBCL.

48. The bispecific antibody of any one of embodiments 1-47, wherein theDLBCL is follicular lymphoma Grade 3B.

49. The bispecific antibody of any one of embodiments 1-48, wherein thesubject has an International Prognostic Index (IPI) score or Revised-IPIscore ≥3.

50. The bispecific antibody of any one of embodiments 1-49, wherein thesubject has not received prior therapy for DLBCL or follicular lymphomaGrade 3B.

51. The bispecific antibody of any one of embodiments 1-50, wherein thesubject is treated with prophylaxis for cytokine release syndrome (CRS).

52. The bispecific antibody of embodiment 51, wherein the prophylaxiscomprises administering a corticosteroid to the subject.

53. The bispecific antibody of embodiment 52, wherein the corticosteroidis administered on the same day as the bispecific antibody.

54. The bispecific antibody of embodiment 53, wherein the corticosteroidis further administered on the second, third, and fourth days afteradministering the bispecific antibody.

55. The bispecific antibody of any one of embodiments 52-54, wherein thecorticosteroid is prednisone.

56. The bispecific antibody of embodiment 55, wherein the prednisone isadministered at an intravenous dose of 100 mg, or equivalent thereof,including oral dose.

57. The bispecific antibody of any one of embodiments 52-54, wherein theprednisone from R-CHOP serves as the corticosteroid for prophylaxis forCRS.

58. The bispecific antibody of embodiment 57, wherein if the prednisonefrom R-CHOP is administered more than 120 minutes before administrationof the bispecific antibody, then the subject is administered prednisoneor an equivalent about 30-120 minutes prior to administration of thebispecific antibody.

59. The bispecific antibody of any one of embodiments 1-58, wherein thesubject is administered premedication to reduce reactions to injections.

60. The bispecific antibody of embodiment 59, wherein the premedicationcomprises an antihistamine.

61. The bispecific antibody of embodiment 60, wherein the antihistamineis diphenhydramine.

62. The bispecific antibody of embodiment 61, wherein thediphenhydramine is administered at an intravenous or oral dose of 50 mg,or equivalent thereof.

63. The bispecific antibody of any one of embodiments 59-62, wherein thepremedication comprises an antipyretic.

64. The bispecific antibody of any one of embodiment 63, wherein theantipyretic is acetaminophen.

65. The bispecific antibody of embodiment 64, wherein the acetaminophenis administered at an oral dose of 650 mg to 1000 mg, or equivalentthereof.

66. The bispecific antibody of any one of embodiments 59-65, wherein thepremedication is administered on the same day as the bispecificantibody.

67. The bispecific antibody of any one of embodiments 51-66, wherein theprophylaxis is administered in cycle 1 and start of cycle 2 of the21-day cycles.

68. The bispecific antibody of any one of embodiments 59-66, wherein thepremedication is administered in cycle 1 and start of cycle 2 of the21-day cycles.

69. The bispecific antibody of any one of embodiments 51-68, wherein theprophylaxis is administered during the second and third administrationsof the bispecific antibody during cycle 2 of the 21-day cycles when thesubject experiences CRS greater than grade 1 after the firstadministration of the bispecific antibody in cycle 2 of the 21-daycycles.

70. The bispecific antibody of embodiment 69, wherein the prophylaxis iscontinued in a subsequent cycle, when in the last administration of thebispecific antibody of the previous cycle, the subject experiences CRSgreater than grade 1.

71. The bispecific antibody of any one of embodiments 59-70, wherein thepremedication is administered during cycle 2 of the 21-day cycles.

72. The bispecific antibody of embodiment 71, wherein the premedicationis administered during subsequent cycles.

73. The bispecific antibody of any one of embodiments 1-72, wherein thesubject is administered antibiotics if the subject develops Grade 1 CRS.

74. The bispecific antibody of any one of embodiments 1-72, wherein thesubject is administered a vasopressor if the subject develops Grade 2 orGrade 3 CRS.

75. The bispecific antibody of any one of embodiments 1-72, wherein thesubject is administered at least two vasopressors if the subjectdevelops Grade 4 CRS.

76. The bispecific antibody of any one of embodiments 1-75, wherein thesubject is administered tocilizumab if the subject develops Grade 2,Grade 3, or Grade 4 CRS.

77. The bispecific antibody of embodiment 76, wherein the subject isfurther administered a steroid.

78. The bispecific antibody of embodiment 77, wherein the steroid isdexamethasone.

79. The bispecific antibody of embodiment 77, wherein the steroid ismethylprednisolone.

80. The bispecific antibody of any one of embodiments 76-79, whereintocilizumab is switched to an anti-IL-6 antibody (e.g., siltuximab) ifthe subject is refractory to tocilizumab.

81. The bispecific antibody of any one of embodiments 76-79, whereintocilizumab is switched to an IL-1R antagonist (e.g., anakinra) if thesubject is refractory to tocilizumab.

82. The bispecific antibody of any one of embodiments 1-81, wherein thesubject is treated with prophylaxis for tumor lysis syndrome (TLS).

83. The bispecific antibody of embodiment 82, wherein the prophylaxisfor TLS comprises administering one or more uric acid reducing agentsprior to administration of the bispecific antibody.

84. The bispecific antibody of embodiment 83, wherein the one or moreuric acid reducing agents comprise rasburicase and/or allopurinol.

85. The bispecific antibody of any one of embodiments 1-84, wherein thesubject achieves a complete response, a partial response, or stabledisease.

86. The bispecific antibody of any one of embodiments 1-85, wherein:

-   -   (i) the first antigen-binding region of the bispecific antibody        comprises VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid        sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively,        and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid        sequences set forth in SEQ ID NO: 4, the sequence GTN, and SEQ        ID NO: 5, respectively; and    -   (ii) the second antigen-binding region of the bispecific        antibody comprises VHCDR1, VHCDR2, and VHCDR3 comprising the        amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10,        respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the        amino acid sequences set forth in SEQ ID NO: 11, the sequence        DAS, and SEQ ID NO: 12, respectively.

87. The bispecific antibody of any one of embodiments 1-86, wherein:

-   -   (i) the first antigen-binding region of the bispecific antibody        comprises a VH region comprising the amino acid sequence of SEQ        ID NO: 6, and the VL region comprising the amino acid sequence        of SEQ ID NO: 7; and    -   (ii) the second antigen-binding region of the bispecific        antibody comprises a VH region comprising the amino acid        sequence of SEQ ID NO: 13, and the VL region comprising the        amino acid sequence of SEQ ID NO: 14.

88. The bispecific antibody of any one of embodiments 1-87, wherein thefirst binding arm of the bispecific antibody is derived from a humanizedantibody, preferably from a full-length IgG1,λ (lambda) antibody.

89. The bispecific antibody of embodiment 88, wherein the first bindingarm of the bispecific antibody comprises a λ light chain constant regioncomprising the amino acid sequence set forth in SEQ ID NO: 22.

90. The bispecific antibody of any one of embodiments 1-89, wherein thesecond binding arm of the bispecific antibody is derived from a humanantibody, preferably from a full-length IgG1,κ (kappa) antibody.

91. The bispecific antibody of embodiment 90, wherein the second bindingarm comprises a κ light chain constant region comprising the amino acidsequence set forth in SEQ ID NO: 23.

92. The bispecific antibody of any one of embodiments 1-91, wherein thebispecific antibody is a full-length antibody with a human IgG1 constantregion.

93. The bispecific antibody of any one of embodiments 1-92, wherein thebispecific antibody comprises an inert Fc region.

94. The bispecific antibody of any one of embodiments 1-93, wherein thebispecific antibody comprises a first heavy chain and a second heavychain, wherein in both the first and second heavy chains, the aminoacids in the positions corresponding to positions L234, L235, and D265in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E,and A, respectively.

95. The bispecific antibody of any one of embodiments 1-94, wherein thebispecific antibody comprises a first heavy chain and a second heavychain, wherein in the first heavy chain, the amino acid in the positioncorresponding to F405 in the human IgG1 heavy chain constant region ofSEQ ID NO: 15 is L, and wherein in the second heavy chain, the aminoacid in the position corresponding to K409 in the human IgG1 heavy chainconstant region of SEQ ID NO: 15 is R, or vice versa.

96. The bispecific antibody of any one of embodiments 1-95, wherein thebispecific antibody comprises a first heavy chain and a second heavychain, wherein

-   -   (i) in both the first and second heavy chains, the amino acids        in the positions corresponding to positions L234, L235, and D265        in the human IgG1 heavy chain constant region of SEQ ID NO: 15        are F, E, and A, respectively, and    -   (ii) in the first heavy chain, the amino acid in the position        corresponding to F405 in the human IgG1 heavy chain constant        region of SEQ ID NO: 15 is L, and wherein in the second heavy        chain, the amino acid in the position corresponding to K409 in        the human IgG1 heavy chain constant region of SEQ ID NO: 15 is        R, or vice versa.

97. The bispecific antibody of embodiment 96, wherein the bispecificantibody comprises heavy chain constant regions comprising the aminoacid sequences of SEQ ID NOs: 19 and 20.

98. The bispecific antibody of any one of embodiments 1-97, wherein thebispecific antibody comprises a heavy chain and a light chain comprisingthe amino acid sequences set forth in SEQ ID NOs: 24 and 25,respectively, and a heavy chain and a light chain comprising the aminoacid sequences set forth in SEQ ID NOs: 26 and 27, respectively.

99. The bispecific antibody of any one of embodiments 1-98, wherein thebispecific antibody comprises a heavy chain and a light chain consistingof the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and aheavy chain and a light chain consisting of the amino acid sequence ofSEQ ID NOs: 26 and 27, respectively.

100. The bispecific antibody of any one of embodiments 1-99, wherein thebispecific antibody is epcoritamab, or a biosimilar thereof.

The present disclosure is further illustrated by the following examples,which should not be construed as further limiting. The contents of allfigures and all references, Genbank sequences, journal publications,patents, and published patent applications cited throughout thisapplication are expressly incorporated herein by reference.

1a. A method of treating diffuse large B-cell lymphoma (DLBCL) in ahuman subject, the method comprising administering to the subject abispecific antibody, and an effective amount of (a) rituximab, (b)cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone,wherein the a bispecific antibody comprises:

-   -   (i) a first binding arm comprising a first antigen-binding        region which binds to human CD3ε (epsilon) and comprises a        variable heavy chain (VH) region and a variable light chain (VL)        region, wherein the VH region comprises the CDR1, CDR2 and CDR3        sequences that are in the VH region sequence of SEQ ID NO: 6,        and the VL region comprises the CDR1, CDR2 and CDR3 sequences        that are in the VL region sequence of SEQ ID NO: 7; and    -   (ii) a second binding arm comprising a second antigen-binding        region which binds to human CD20 and comprises a VH region and a        VL region, wherein the VH region comprises the CDR1, CDR2 and        CDR3 sequences that are in the VH region sequence of SEQ ID NO:        13, and the VL region comprises the CDR1, CDR2 and CDR3        sequences that are in the VL region sequence of SEQ ID NO: 14;    -   wherein the bispecific antibody is administered at a dose of 24        mg or 48 mg, and wherein rituximab, cyclophosphamide,        doxorubicin, vincristine, prednisone, and the bispecific        antibody are administered in 21-day cycles.

2a. The method of embodiment 1a, wherein the bispecific antibody isadministered at a dose of 24 mg.

3a. The method of embodiment 1a, wherein the bispecific antibody isadministered at a dose of 48 mg.

4a. The method of any one of embodiments 1a-3a, wherein the bispecificantibody is administered once every week (weekly administration).

5a. The method of embodiment 4a, wherein the weekly administration of 24mg or 48 mg is performed for three and one-third 21-day cycles.

6a. The method of embodiment 4a or 5a, wherein after the weeklyadministration, the bispecific antibody is administered once every threeweeks.

7a. The method of embodiment 6a, wherein the administration once everythree weeks is performed for two or four 21-day cycles.

8a. The method of embodiment 7a, wherein after the administration onceevery three weeks, the bispecific antibody is administered once everyfour weeks in 28-day cycles.

9a. The method of embodiment 8a, wherein the administration once everyfour weeks is performed for up to one year total duration of treatmentwith the bispecific antibody.

10a. The method of any one of embodiments 4a-9a, wherein prior to theweekly administration of 24 mg or 48 mg, a priming dose of thebispecific antibody is administered in cycle 1 of the 21-day cycles.

11a. The method of embodiment 10a, wherein the priming dose isadministered two weeks prior to administering the first weekly dose of24 mg or 48 mg.

12a. The method of embodiment 10a or 11a, wherein the priming dose is0.16 mg.

13a. The method of any one of embodiments 10a-12a, wherein afteradministering the priming dose and prior to administering the firstweekly dose of 24 mg or 48 mg, an intermediate dose of the bispecificantibody is administered.

14a. The method of embodiment 13a, wherein the priming dose isadministered on day 1 and the intermediate dose is administered on day 8before the first weekly dose of 24 mg or 48 mg on day 15 of cycle 1.

15a. The method of embodiment 13a or 14a, wherein the intermediate doseis 0.8 mg.

16a. The method of any one of embodiments 1a-15a, wherein rituximab isadministered once every three weeks.

17a. The method of embodiment 16a, wherein the administration ofrituximab once every three weeks is performed for six or eight 21-daycycles.

18a. The method of any one of embodiments 1a-17a, wherein rituximab isadministered at a dose of 375 mg/m².

19a. The method of any one of embodiments 1a-18a, whereincyclophosphamide is administered once every three weeks.

20a. The method of embodiment 19a, wherein the administration ofcyclophosphamide once every three weeks is performed for six or eight21-day cycles.

21a. The method of any one of embodiments 1a-20a, whereincyclophosphamide is administered at a dose of 750 mg/m².

22a. The method of any one of embodiments 1a-21a, wherein doxorubicin isadministered once every three weeks.

23a. The method of embodiment 22a, wherein the administration ofdoxorubicin once every three weeks is performed for six or eight 21-daycycles.

24a. The method of any one of embodiments 1a-23a, wherein doxorubicin isadministered at a dose of 50 mg/m².

25a. The method of any one of embodiments 1a-24a, wherein vincristine isadministered once every three weeks.

26a. The method of embodiment 25a, wherein the administration ofvincristine once every three weeks is performed for six or eight 21-daycycles.

27a. The method of any one of embodiments 1a-26a, wherein vincristine isadministered at a dose of 1.4 mg/m².

28a. The method of any one of embodiments 1a-27a, wherein prednisone isadministered once a day from day 1 to day 5 of the 21-day cycles.

29a. The method of embodiment 28a, wherein prednisone is administeredfor six or eight 21-day cycles.

30a. The method of any one of embodiments 1a-29a, wherein prednisone isadministered at a dose of 100 mg/day.

31a. The method of any one of embodiments 1a-30a, wherein rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, and thebispecific antibody are administered on the same day (e.g., on day 1 ofcycles 1-6 or cycles 1-8 of the 21-day cycles).

32a. The method of any one of embodiments 1a-31a, wherein the dosingschedule for rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone, and the bispecific antibody is as shown in Table 2.

33a. The method of any one of embodiments 1a, 2a, and 4a-32a, whereinadministration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 24 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

34a. The method of any one of embodiments 1a and 3a-32a, whereinadministration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5 and 6, a dose of 48 mg is administered on            day 1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-6; and    -   (c) prednisone is administered on days 1-5 in cycles 1-6.

35a. The method of embodiment 33a or 34a wherein the bispecific antibodyis administered once every four weeks in 28-day cycles on day 1 fromcycle 7.

36a. The method of any one of embodiments 1a, 2a, and 4a-32a, whereinadministration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 24 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 24 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 24 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

37a. The method of any one of embodiments 1 and 3a-32a, whereinadministration is performed in 21-day cycles, and wherein:

-   -   (a) the bispecific antibody is administered as follows:        -   (i) in cycle 1, a priming dose of 0.16 mg is administered on            day 1, an intermediate dose of 0.8 mg is administered on day            8, and a dose of 48 mg is administered on day 15;        -   (ii) in cycles 2-4, a dose of 48 mg is administered on days            1, 8, and 15;        -   (iii) in cycles 5-8, a dose of 48 mg is administered on day            1;    -   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine        are administered on day 1 in cycles 1-8; and    -   (c) prednisone is administered on days 1-5 in cycles 1-8.

38a. The method of embodiment 36a or 37a, wherein the bispecificantibody is administered once every four weeks in 28-day cycles on day 1from cycle 9.

39a. The method of any one of embodiments 1a-38a, wherein the bispecificantibody is administered subcutaneously.

40a. The method of any one of embodiments 1a-39a, wherein rituximab isadministered intravenously.

41a. The method of any one of embodiments 1a-40a, whereincyclophosphamide is administered intravenously.

42a. The method of any one of embodiments 1a-41a, wherein doxorubicin isadministered intravenously.

43a. The method of any one of embodiments 1a-42a, wherein vincristine isadministered intravenously.

44a. The method of any one of embodiments 1a-43a, wherein prednisone isadministered intravenously or orally.

45a. The method of any one of embodiments 1a-44a, wherein rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, and thebispecific antibody are administered sequentially.

46a. The method of any one of embodiments 1a-45a, wherein prednisone isadministered first, rituximab is administered second, cyclophosphamideis administered third, doxorubicin is administered fourth, vincristineis administered fifth, and the bispecific antibody is administered lastif rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone,and the bispecific antibody are administered on the same day.

47a. The method of any one of embodiments 1a-46a, wherein the DLBCL isdouble-hit or triple-hit DLBCL.

48a. The method of any one of embodiments 1a-47a, wherein the DLBCL isfollicular lymphoma Grade 3B.

49a. The method of any one of embodiments 1a-48a, wherein the subjecthas an International Prognostic Index (IPI) score or Revised-IPI score≥3.

50a. The method of any one of embodiments 1a-49a, wherein the subjecthas not received prior therapy for DLBCL or follicular lymphoma Grade3B.

51a. The method of any one of embodiments 1a-50a, wherein the subject istreated with prophylaxis for cytokine release syndrome (CRS).

52a. The method of embodiment 51a, wherein the prophylaxis comprisesadministering a corticosteroid to the subject.

53a. The method of embodiment 52a, wherein the corticosteroid isadministered on the same day as the bispecific antibody.

54a. The method of embodiment 53a, wherein the corticosteroid is furtheradministered on the second, third, and fourth days after administeringthe bispecific antibody.

55a. The method of any one of embodiments 52a-54a, wherein thecorticosteroid is prednisone.

56a. The method of embodiment 55a, wherein the prednisone isadministered at an intravenous dose of 100 mg, or equivalent thereof,including oral dose.

57a. The method of any one of embodiments 52a-54a, wherein theprednisone from R-CHOP serves as the corticosteroid for prophylaxis forCRS.

58a. The method of embodiment 57a, wherein if the prednisone from R-CHOPis administered more than 120 minutes before administration of thebispecific antibody, then the subject is administered prednisone or anequivalent about 30-120 minutes prior to administration of thebispecific antibody.

59a. The method of any one of embodiments 1a-58a, wherein the subject isadministered premedication to reduce reactions to injections.

60a. The method of embodiment 59a, wherein the premedication comprisesan antihistamine.

61a. The method of embodiment 60a, wherein the antihistamine isdiphenhydramine.

62a. The method of embodiment 61a, wherein the diphenhydramine isadministered at an intravenous or oral dose of 50 mg, or equivalentthereof.

63a. The method of any one of embodiments 59a-62a, wherein thepremedication comprises an antipyretic.

64a. The method of embodiment 63a, wherein the antipyretic isacetaminophen.

65a. The method of embodiment 64a, wherein the acetaminophen isadministered at an oral dose of 650 mg to 1000 mg, or equivalentthereof.

66a. The method of any one of embodiments 59a-65a, wherein thepremedication is administered on the same day as the bispecificantibody.

67a. The method of any one of embodiments 51a-66a, wherein theprophylaxis is administered in cycle 1 and start of cycle 2 of the21-day cycles.

68a. The method of any one of embodiments 59a-66a, wherein thepremedication is administered in cycle 1 and start of cycle 2 of the21-day cycles.

69a. The method of any one of embodiments 51a-68a, wherein theprophylaxis is administered during the second and third administrationsof the bispecific antibody during cycle 2 of the 21-day cycles when thesubject experiences CRS greater than grade 1 after the firstadministration of the bispecific antibody in cycle 2 of the 21-daycycles.

70a. The method of embodiment 69a, wherein the prophylaxis is continuedin a subsequent cycle, when in the last administration of the bispecificantibody of the previous cycle, the subject experiences CRS greater thangrade 1.

71a. The method of any one of embodiments 59a-70a, wherein thepremedication is administered during cycle 2 of the 21-day cycles.

72a. The method of embodiment 71a, wherein the premedication isadministered during subsequent cycles.

73a. The method of any one of embodiments 1a-72a, wherein the subject isadministered antibiotics if the subject develops Grade 1 CRS.

74a. The method of any one of embodiments 1a-72a, wherein the subject isadministered a vasopressor if the subject develops Grade 2 or Grade 3CRS.

75a. The method of any one of embodiments 1a-72a, wherein the subject isadministered at least two vasopressors if the subject develops Grade 4CRS.

76a. The method of any one of embodiments 1a-75a, wherein the subject isadministered tocilizumab if the subject develops Grade 2, Grade 3, orGrade 4 CRS.

77a. The method of embodiment 76a, wherein the subject is furtheradministered a steroid.

78a. The method of embodiment 77a, wherein the steroid is dexamethasone.

79a. The method of embodiment 77a, wherein the steroid ismethylprednisolone.

80a. The method of any one of embodiments 76a-79a, wherein tocilizumabis switched to an anti-IL-6 antibody (e.g., siltuximab) if the subjectis refractory to tocilizumab.

81a. The method of any one of embodiments 76a-79a, wherein tocilizumabis switched to an IL-1R antagonist (e.g., anakinra) if the subject isrefractory to tocilizumab.

82a. The method of any one of embodiments 1a-81a, wherein the subject istreated with prophylaxis for tumor lysis syndrome (TLS).

83a. The method of embodiment 82a, wherein the prophylaxis for TLScomprises administering one or more uric acid reducing agents prior toadministration of the bispecific antibody.

84a. The method of embodiment 83a, wherein the one or more uric acidreducing agents comprise rasburicase and/or allopurinol.

85a. The method of any one of embodiments 1a-84a, wherein the subjectachieves a complete response, a partial response, or stable disease.

86a. The method of any one of embodiments 1a-85a, wherein:

-   -   (i) the first antigen-binding region of the bispecific antibody        comprises VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid        sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively,        and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid        sequences set forth in SEQ ID NO: 4, the sequence GTN, and SEQ        ID NO: 5, respectively; and    -   (ii) the second antigen-binding region of the bispecific        antibody comprises VHCDR1, VHCDR2, and VHCDR3 comprising the        amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10,        respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the        amino acid sequences set forth in SEQ ID NO: 11, the sequence        DAS, and SEQ ID NO: 12, respectively.

87a. The method of any one of embodiments 1a-86a, wherein:

-   -   (i) the first antigen-binding region of the bispecific antibody        comprises a VH region comprising the amino acid sequence of SEQ        ID NO: 6, and the VL region comprising the amino acid sequence        of SEQ ID NO: 7; and    -   (ii) the second antigen-binding region of the bispecific        antibody comprises a VH region comprising the amino acid        sequence of SEQ ID NO: 13, and the VL region comprising the        amino acid sequence of SEQ ID NO: 14.

88a. The method of any one of embodiments 1a-87a, wherein the firstbinding arm of the bispecific antibody is derived from a humanizedantibody, preferably from a full-length IgG1,λ (lambda) antibody.

89a. The method of embodiment 88a, wherein the first binding arm of thebispecific antibody comprises a λ light chain constant region comprisingthe amino acid sequence set forth in SEQ ID NO: 22.

90a. The method of any one of embodiments 1a-89a, wherein the secondbinding arm of the bispecific antibody is derived from a human antibody,preferably from a full-length IgG1,κ (kappa) antibody.

91a. The method of embodiment 90a, wherein the second binding armcomprises a κ light chain constant region comprising the amino acidsequence set forth in SEQ ID NO: 23.

92a. The method of any one of embodiments 1a-91a, wherein the bispecificantibody is a full-length antibody with a human IgG1 constant region.

93a. The method of any one of embodiments 1a-92a, wherein the bispecificantibody comprises an inert Fc region.

94a. The method of any one of embodiments 1a-93a, wherein the bispecificantibody comprises a first heavy chain and a second heavy chain, whereinin both the first and second heavy chains, the amino acids in thepositions corresponding to positions L234, L235, and D265 in the humanIgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A,respectively.

95a. The method of any one of embodiments 1a-94a, wherein the bispecificantibody comprises a first heavy chain and a second heavy chain, whereinin the first heavy chain, the amino acid in the position correspondingto F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15is L, and wherein in the second heavy chain, the amino acid in theposition corresponding to K409 in the human IgG1 heavy chain constantregion of SEQ ID NO: 15 is R, or vice versa.

96a. The method of any one of embodiments 1a-95a, wherein the bispecificantibody comprises a first heavy chain and a second heavy chain, wherein

-   -   (i) in both the first and second heavy chains, the amino acids        in the positions corresponding to positions L234, L235, and D265        in the human IgG1 heavy chain constant region of SEQ ID NO: 15        are F, E, and A, respectively, and    -   (ii) in the first heavy chain, the amino acid in the position        corresponding to F405 in the human IgG1 heavy chain constant        region of SEQ ID NO: 15 is L, and wherein in the second heavy        chain, the amino acid in the position corresponding to K409 in        the human IgG1 heavy chain constant region of SEQ ID NO: 15 is        R, or vice versa.

97a. The method of embodiment 96, wherein the bispecific antibodycomprises heavy chain constant regions comprising the amino acidsequences of SEQ ID NOs: 19 and 20.

98a. The method of any one of embodiments 1a-97a, wherein the bispecificantibody comprises a heavy chain and a light chain comprising the aminoacid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and aheavy chain and a light chain comprising the amino acid sequences setforth in SEQ ID NOs: 26 and 27, respectively.

99a. The method of any one of embodiments 1a-98a, wherein the bispecificantibody comprises a heavy chain and a light chain consisting of theamino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavychain and a light chain consisting of the amino acid sequence of SEQ IDNOs: 26 and 27, respectively.

100a. The method of any one of embodiments 1a-99a, wherein thebispecific antibody is epcoritamab, or a biosimilar thereof.

EXAMPLES DuoBody-CD3xCD20

DuoBody-CD3xCD20 is a bsAb recognizing the T-cell antigen CD3 and theB-cell antigen CD20. DuoBody-CD3xCD20 triggers potent T-cell-mediatedkilling of CD20-expressing cells. DuoBody-CD3xCD20 has a regular IgG1structure.

Two parental antibodies, IgG1-CD3-FEAL, a humanized IgG1λ, CD3ε-specificantibody having heavy and light chain sequences as listed in SEQ ID NOs:24 and 25, respectively, and IgG1-CD20-FEAR, derived from human IgG1κCD20-specific antibody 7D8 having heavy and light chain sequences aslisted in SEQ ID NOs: 26 and 27, respectively, were manufactured asseparate biological intermediates. Each parental antibody contains oneof the complementary mutations in the CH3 domain required for thegeneration of DuoBody molecules (F405L and K409R, respectively). Theparental antibodies comprised three additional mutations in the Fcregion (L234F, L235E and D265A; FEA). The parental antibodies wereproduced in mammalian Chinese hamster ovary (CHO) cell lines usingstandard suspension cell cultivation and purification technologies.DuoBody-CD3xCD20 was subsequently manufactured by a controlled Fab-armexchange (cFAE) process (Labrijn et al. 2013, Labrijn et al. 2014,Gramer et al. 2013). The parental antibodies are mixed and subjected tocontrolled reducing conditions. This leads to separation of the parentalantibodies that, under re-oxidation, re-assemble. This way, highly purepreparations of DuoBody-CD3xCD20 (˜93-95%) were obtained. After furtherpolishing/purification, final product was obtained, close to 100% pure.The DuoBody-CD3xCD20 concentration was measured by absorbance at 280 nm,using the theoretical extinction coefficient ε=1.597 mL·mg⁻¹cm⁻¹. Thefinal product was stored at 4° C. The product has an internationalproprietary name of epcoritamab.

Epcoritamab is prepared (5 mg/mL or 60 mg/mL) as a sterile clearcolorless to slightly yellow solution supplied as concentrate forsolution for subcutaneous (SC) injection. Epcoritamab contains bufferingand tonicifying agents. All excipients and amounts thereof in theformulated product are pharmaceutically acceptable for subcutaneousinjection products. Appropriate doses are reconstituted to a volume ofabout 1 mL for subcutaneous injection.

Example 1: Anti-Tumor Activity of Epcoritamab in the Presence ofAnti-CD20 Antibody In Vivo and in NHL Patient-Derived Samples afterAnti-CD20 Treatment

The effects of the presence of an anti-CD20 antibody on the anti-tumoractivity of epcoritamab in a humanized mouse xenograft model has beendescribed in Engelberts et al., EBioMedicine 2020; 52:10265, assummarized below.

Epcoritamab was found to effectively reduce tumor growth in thexenograft model (NOD-SCID mice injected with CD20-expressing Raji-luctumor cells and PBMCs), even in the presence of an excess of a rituximabvariant with an inert Fc domain (IgG1-RTX-FEAR, containing L234F, L235E,D265A, and K409R mutations). Rituximab and IgG1-CD20, of which the CD20arm of epcoritamab is derived, compete for CD20 binding even though theybind to a different epitope, indicating that epcoritamab is able toinduce effective anti-tumor activity in the presence of circulatinganti-CD20 antibodies that can compete for target binding.

Furthermore, epcoritamab induced T-cell-mediated cytotoxicity in primaryDLBCL and follicular lymphoma patient biopsies taken a certain amount oftime after administration of an anti-CD20 antibody (Van der Horst etal., Blood (2019) 134 (Supplement_1): 4066). Even in a biopsy taken 2weeks after administering anti-CD20 antibody, epcoritamab was able toinduce up to 40% tumor cell kill.

Example 2: Impact of CHOP on In Vitro T Cell-Mediated CytotoxicityInduced by Epcoritamab

CHOP is often used to treat DLBCL and FL. This experiment was performedto test the impact of CHOP components separately to evaluate eachcomponent's effect on epcoritamab-induced T-cell-mediated cytotoxicity.

Briefly, T cells were pre-incubated with cyclophosphamide, doxorubicin,vincristine, or prednisone for 16 hours and subsequently used in acytotoxicity assay with epcoritamab and CD20-expressing Daudi cells astarget cells (E:T ratio 2:1), in which cyclophosphamide, doxorubicin,vincristine, or prednisone was added in the same concentration as duringpre-incubation, respectively. Data are presented as percent viabletarget cells (CD4-CD8-CD22+), normalized to medium control (no Ab, noCHOP component). Since doxorubicin pre-treatment affected the viabilityof the T cells, not all concentrations of epcoritamab could be tested.

FIGS. 1A-1D show in the left panels dose response curves forDuoBody-CD3xCD20 for a representative donor, the right panels show theresponse to a dose of 333 ng/ml of DuoBody-CD3xCD20 for four differentdonors, with and without various concentrations of the CHOP components.Pretreatment of T cells with cyclophosphamide, vincristine, orprednisone, respectively, did not impact T cell viability (data notshown). As said, pretreatment with doxorubicin led to a reduction in Tcell viability (not shown), though the degree observed in-vitro appearedexaggerated as compared with what was observed in patients treated withR-CHOP (Oncology 2016; 91: 302-10 and Hematol Oncol 2011; 29:5-9). Asshown in FIGS. 1A, 1C, and 1D, T cells pretreated with cyclophosphamide(A), vincristine (C), or prednisone (D) were able to mediate anepcoritamab-induced cytotoxic response against the CD20-expressingtarget cells, as shown by the dose-dependent cytotoxicity (in the leftpanels) and the very low percentages of viable B cells left afterincubation (in the right panels). As shown in FIG. 1B, the remaining Tcells pre-treated with doxorubicin were also able to mediateepcoritamab-induced cytotoxicity against target cells indicating thatthe remaining T cells were functional.

Taken together, the data and observations above show that epcoritamabcan be combined with CHOP and R-CHOP, as rituximab does not interferewith epcoritamab activity, to induce highly effective anti-tumoractivity against CD20-expressing target cells.

Example 3: A Phase 1b, Open-Label, Safety and Efficacy Study ofEpcoritamab in Combination with Standard-of-Care R-CHOP for theTreatment of Previously Untreated, High-Risk (IPI or R-IPI≥3) DLBCL

An open-label, 2-part (dose escalation and expansion), multinational,multicenter interventional study is conducted to evaluate the safety,tolerability, PK, pharmacodynamics/biomarkers, immunogenicity, andpreliminary efficacy of epcoritamab in combination with a standard ofcare regimen of R-CHOP in subjects with previously untreated DLBCL.

Summary of Ongoing Clinical Trial with Epcoritamab

Epcoritamab as monotherapy is currently in a clinical trial for thetreatment of relapsed/refractory (R/R) B-NHL (ClinicalTrials.govIdentifier: NCT03625037). Preliminary data suggest that the drug istolerated at doses up to at least 48 mg, including 60 mg, in R/R B-NHLpatients, with no dose-limiting toxicities reported.

Objectives Dose Escalation

The primary objective of the dose escalation part is to evaluate thesafety and tolerability of epcoritamab in combination with R-CHOP(endpoints: incidence of dose-limiting toxicities (DLTs), incidence andseverity of adverse events (AEs), incidence and severity of changes inlaboratory values, and incidence of dose interruptions and delays).

Secondary objectives of the dose escalation part include characterizingthe PK properties of epcoritamab (endpoints: PK parameters, includingclearance, volume of distribution, AUC0-last, AUC0-x, Cmax, Tmax,predose values, and half-life), evaluating pharmacodynamic markerslinked to efficacy and the mechanism of action of epcoritamab(endpoints: pharmacodynamic markers in blood samples and within tumor),evaluating immunogenicity (endpoint: incidence of anti-drug antibodies(ADAs) to epcoritamab), and assessing the preliminary anti-tumoractivity of epcoritamab in combination with R-CHOP (endpoints: overallresponse rate (ORR) by Lugano criteria and LYRIC, duration of response(DOR) by Lugano criteria and LYRIC, time to response (TTR) by Luganocriteria and LYRIC, progression free survival (PFS) by Lugano criteriaand LYRIC, overall survival (OS), time to next anti-lymphoma therapy(TTNT), and rate and duration of minimal residual disease (MRD)negativity).

Exploratory objectives of the dose escalation part include assessingpotential biomarkers predictive of clinical response to epcoritamab(endpoints: CD3, CD20, and other molecular/phenotypic markerspre-treatment and during treatment, DNA mutation status, and geneprofile).

Expansion

The primary objective of the expansion part is to assess the preliminaryanti-tumor activity of epcoritamab in combination with R-CHOP (endpoint:ORR by Lugano criteria).

Secondary objectives of the expansion part include evaluating thepreliminary anti-tumor activity of epcoritamab in combination withR-CHOP (endpoints: endpoints: DOR by Lugano criteria and LYRIC, TTR byLugano criteria and LYRIC, PFS by Lugano criteria and LYRIC, ORR byLYRIC, OS, TTNT, and rate and duration of minimal residual disease (MRD)negativity), further evaluating the safety and tolerability ofepcoritamab in combination with R-CHOP (endpoints: incidence andseverity of changes in laboratory values, and incidence of doseinterruptions and delays), characterizing the PK properties ofepcoritamab (PK parameters, including clearance, volume of distribution,AUC0-last, AUC0-x, Cmax, Tmax, predose values, and half-life),evaluating pharmacodynamic markers linked to efficacy and mechanism ofaction of epcoritamab (endpoints: pharmacodynamic markers in bloodsamples and within tumor), and evaluating immunogenicity (endpoint:incidence of ADAs to epcoritamab).

Exploratory objectives of the expansion part include assessing potentialbiomarkers predictive of clinical response to epcoritamab (endpoints:expression of CD20 in tumors, evaluation of molecular and genetic tumormarkers, immune populations, phenotype and function in tumors and blood,and DNA mutation status and gene profile), and evaluatingpatient-reported outcomes (PROs) (endpoint: changes in lymphoma symptomsand general health status as evaluated by the FACT-Lym).

Study Design Overview

The trial is conducted in 2 parts: dose escalation (Part 1) andexpansion (Part 2). Subjects participate in only one part. A schematicof the overall trial design is shown in FIG. 2 . Both parts consist of ascreening period, a treatment period, a safety follow-up period, and asurvival follow-up period.

Dose Escalation (Part 1) and Expansion (Part 2)

The Part 1 dose escalation assesses the initial safety, tolerability,and clinical activity of epcoritamab in combination with R-CHOP.Epcoritamab is initially be administered in combination with R-CHOP in a3-subject cohort. DLTs are evaluated during the first 28 days. Dependingon the number of DLTs observed in the initial 3 subjects, administrationof epcoritamab (full dose: 48 mg or 24 mg) in combination with R-CHOP isperformed in an additional 3 subjects as shown in FIG. 3 .

In Part 2, epcoritamab is administered (with the dosing regimendetermined in the dose-escalation part) in combination with R-CHOP. Theexpansion will include 20 subjects in order to evaluate the preliminaryclinical activity of the combination, in addition to safety,tolerability, PK, pharmacodynamic, and immunogenicity data.

In both Part 1 and Part 2, epcoritamab is administered as a subcutaneous(SC) injection (24 mg or 48 mg; step-up dosing) for up to one year totalduration of treatment with the bispecific antibody from initiation ofR-CHOP, with 6 (Table 2a), or 8 (Table 2b) of the cycles in combinationwith R-CHOP, as follows:

TABLE 2(a) Dosing schedule (6 cycles with R-CHOP) Cycle numberEpcoritamab R-CHOP 21-day cycles 1   QW, step-up dosing Q3W 2-4 QW Q3W5-6 Q3W Q3W 28-day cycles 7+ Q4W —

TABLE 2(b) Dosing schedule (8 cycles with R-CHOP) Cycle numberEpcoritamab R-CHOP 21-day cycles 1   QW, step-up dosing Q3W 2-4 QW Q3W5-8 Q3W Q3W 28-day cycles 9+ Q4W —QW: once a week (days 1, 8, and 15), Q3W: once every 3 weeks (day 1),Q4W: once every 4 weeks (day 1)

A step-up dosing method is used for epcoritamab to mitigate thepotential for CRS: priming dose (0.16 mg) on cycle 1 day 1, followed byintermediate dose (0.8 mg) on cycle 1 day 8, full dose (24 mg or 48 mg)on cycle 1 day 15, and full dose in subsequent cycles. Rituximab (375mg/m²) is administered intravenously on day 1 once every three weeks (Q3W) for cycles 1-6 or 1-8. Cyclophosphamide (750 mg/m²) is administeredintravenously on day 1 once every three weeks (Q3 W) of cycles 1-6 or1-8. Doxorubicin (50 mg/m²) is administered intravenously on day 1 onceevery three weeks (Q3 W) of cycles 1-6 or 1-8. Vincristine (1.4 mg/m²,with a recommended cap of 2 mg) is administered intravenously on day 1once every three weeks (Q3 W) of cycles 1-6 or 1-8. Prednisone (100mg/day) is administered intravenously or orally on five consecutive days(days 1-5) every three weeks (Q3 W) of cycles 1-6 or 1-8.

The order of treatments are as follows:

TABLE 3 Treatment administration order Dosing order Treatment DosePre-Meds Pre-medications (prednisone As described in Table 4 componentof R-CHOP may serve as corticosteriod premedication/CRS prophylaxis) 1Prednisone 100 mg 2 Rituximab* 375 mg/m² 3 Cyclophosphamide* 750 mg/m² 4Doxorubicin* 50 mg/m² (hydroxydaunomycin) 5 Vincristine* (Oncovin ®) 1.4mg/m² (max. 2 mg) 6 Epcoritamab 24 mg or 48 mg *Intravenous componentsof R-CHOP may be administered over 2 days, with subsequent epcoritamabadministration on day 2.

Inclusion Criteria

-   -   1. Subject must be at least 18 years of age    -   2. ECOG PS score of 0, 1, or 2    -   3. CD20-positive NHL at representative tumor biopsy    -   4. Measurable disease defined as ≥1 measurable nodal lesion        (long axis >1.5 cm and short axis >1.0 cm) or ≥1 measurable        extra-nodal lesion (long axis >1.0 cm) on CT or MRI    -   5. Acceptable organ function at screening defined as:        -   a. ANC ≥1.0×10⁹/L (growth factor use is allowed)        -   b. Platelet count ≥75×10⁹/L, or ≥50×10⁹/L if bone marrow            infiltration or splenomegaly        -   c. ALT level ≤2.5 times the ULN        -   d. Total bilirubin level ≤2×ULN        -   e. eGFR >50 mL/min (by Cockcroft-Gault Formula)        -   f. PT, INR, and aPTT ≤1.5×ULN, unless receiving            anticoagulant    -   6. Documented DLBCL (de novo or histologically transformed from        indolent lymphomas, except for CLL) according to the 2016 WHO        classification, including:        -   a. DLBCL, NOS        -   b. “Double hit” or “triple hit” DLBCL (technically            classified in WHO 2016 as HGBCL, with MYC and BCL2 and/or            BCL6 translocations)—Other double-/triple-hit lymphomas are            not eligible        -   c. FL Grade 3B    -   7. International Prognostic Index score ≥3    -   8. No prior therapy for DLBCL (or FL Grade 3B) other than        corticosteroids, not exceeding the threshold listed in exclusion        criterion 8.    -   9. Eligible to receive R-CHOP. For subjects aged ≥80 years,        confirm they are eligible to receive R-CHOP according to        protocol, without preplanned dose reductions.    -   10. LVEF within institutional normal limits by multiple-gated        acquisition scan (MUGA) or echocardiography at screening.

Exclusion Criteria

-   -   1. Prior therapy for DLBCL with the exception of nodal biopsy    -   2. Contraindication to any of the individual drugs in the R-CHOP        regimen    -   3. History of severe allergic or anaphylactic reactions to        anti-CD20 mAb therapy or known allergy or intolerance to any        component or excipient of epcoritamab    -   4. Prior treatment with a bispecific antibody targeting CD3 and        CD20    -   5. Chemotherapy, radiation therapy, or major surgery within 4        weeks prior to the first dose of epcoritamab    -   6. Treatment with an investigational drug within 4 weeks or 5        half-lives, whichever is longer, prior to the first dose of        epcoritamab    -   7. Treatment with CAR-T therapy within 30 days prior to first        dose of epcoritamab    -   8. Cumulative dose of corticosteroids ≥140 mg of prednisone or        the equivalent within 2-week    -   period before the first dose of epcoritamab    -   9. Vaccination with live vaccines within 28 days prior to the        first dose of epcoritamab    -   10. Clinically significant cardiac disease, including:        -   a. Myocardial infarction within 1 year prior to the first            dose of epcoritamab, or unstable or uncontrolled            disease/condition related to or affecting cardiac function            (e.g., unstable angina, congestive heart failure, New York            Heart Association Class III-IV), cardiac arrhythmia (CTCAE            Version 4 Grade 2 or higher), or clinically significant ECG            abnormalities        -   b. Screening 12-lead ECG showing a baseline QTcF >470 msec    -   11. Evidence of significant, uncontrolled concomitant diseases        that could affect compliance with the protocol or interpretation        of results    -   12. Known active bacterial, viral, fungal, mycobacterial,        parasitic, or other infection (excluding fungal infections of        nail beds) at trial enrollment or significant infections within        2 weeks prior to the first dose of epcoritamab    -   13. CNS lymphoma or known CNS involvement by lymphoma at        screening as confirmed by MRI/CT scan of the brain and, if        clinically indicated, by lumbar puncture    -   14. Active positive tests for hepatitis B virus or hepatitis C        virus indicating acute or chronic infection    -   15. History of HIV antibody positivity, or tests positive for        HIV at screening    -   16. Positive test results for HTLV-1    -   17. Suspected active or latent tuberculosis    -   18. Past or current malignancy other than inclusion diagnosis,        except for:        -   a. Cervical carcinoma of Stage 1B or less        -   b. Non-invasive basal cell or squamous cell skin carcinoma        -   c. Non-invasive, superficial bladder cancer        -   d. Prostate cancer with a current PSA level <0.1 ng/mL        -   e. Any curable cancer with a CR of >2 years duration    -   19. Neuropathy >grade 1    -   20. Female who is pregnant, breast-feeding, or planning to        become pregnant while enrolled in this trial or within 12 months        after the last dose of epcoritamab    -   21. Male who plans to father a child while enrolled in this        trial or within 12 months after the last dose of epcoritamab    -   22. Subject who has any condition for which participation would        not be in the best interest of the subject (e.g., compromise the        well-being) or that could prevent, limit, or confound the        protocol-specified assessments.

CRS Prophylaxis

Administration of corticosteroids for four days is performed toreduce/prevent the severity of symptoms from potential CRS for each doseof epcoritamab. Prednisone in the R-CHOP regimen serves as thecorticosteroid component of the CRS prophylaxis regimen on days 1-4 ofcycle 1 of the 21-day cycles, but not days 8-11 and 15-18 of cycle 1 ofthe 21-day cycles, which will use prednisolone 100 mg or equivalent forCRS prophylaxis. For administration of epcoritamab in cycle 2 andbeyond, CRS prophylaxis is optional. Prednisone administration can beeither intravenous or oral route with recommended dose or equivalent.

Supportive therapies recommended for treatments containing rituximabinclude:

-   -   Premedication with acetaminophen (650 mg orally),        diphenhydramine (50 to 100 mg IV or orally), and steroids, 30 to        60 minutes before starting each rituximab infusion, to attenuate        infusion reactions    -   Prophylactic treatment for Pneumocystis carinii pneumonia    -   Central nervous system (CNS) prophylaxis; subjects with 1)        involvement of 2 extranodal sites and elevated LDH, or 2)        lymphomatous involvement of the bone marrow, testis, or a        para-meningeal site are considered to be at high risk of        developing CNS disease and should receive CNS prophylaxis. CNS        prophylaxis with IV methotrexate is permitted following        completion of the DLT period (28 days from first dose of study        treatment)

TABLE 4 Pre-medication and CRS prophylaxis CorticosteroidsAntihistamines Antipyretics Cycle 1 1^(st) epcoritamab Day Prednisone100 mg Diphenhydramine Paracetamol administration 01* (or equivalent, IV50 mg IV or oral (PO) (acetaminophen) 650 (priming dose) or oral dose)(or equivalent) to 1000 mg PO (or equivalent) Day Prednisone 100 mg 02(or equivalent IV or oral dose) Day Prednisone 100 mg 03 (or equivalentIV or oral dose) Day Prednisone 100 mg 04 (or equivalent IV or oraldose) Day Prednisone 100 mg 05 (or equivalent IV or oral dose) 2^(nd)epcoritamab Day Prednisone 100 mg Diphenhydramine Paracetamoladministration 08* (or equivalent IV or 50 mg IV or oral (PO)(acetaminophen) 650 (intermediate oral dose) (or equivalent) to 1000 mgPO (or dose) equivalent) Day Prednisone 100 mg 09 (or equivalent IV ororal dose) Day Prednisone 100 mg 10 (or equivalent IV or oral dose) DayPrednisone 100 mg 11 (or equivalent IV or oral dose) 3^(rd) epcoritamabDay Prednisone 100 mg Diphenhydramine Paracetamol administration 15* (orequivalent IV or 50 mg IV or oral (PO) (acetaminophen) 650 (full dose)oral dose) (or equivalent) to 1000 mg PO (or equivalent) Day Prednisone100 mg 16 (or equivalent IV or oral dose) Day Prednisone 100 mg 17 (orequivalent IV or oral dose) Day Prednisone 100 mg 18 (or equivalent IVor oral dose) Cycle 2 4^(th) epcoritamab Day Prednisone 100 mgDiphenhydramine Paracetamol administration 22 (or equivalent IV or 50 mgIV or oral (PO) (acetaminophen) 650 (full dose) oral dose) (orequivalent) to 1000 mg PO (or equivalent) Day Prednisone 100 mg 23 (orequivalent IV or oral dose) Day Prednisone 100 mg 24 (or equivalent IVor oral dose) Day Prednisone 100 mg 25 (or equivalent IV or oral dose)5^(th) epcoritamab Day If CRS > grade 1 Optional Optional administration29* occurs following (full dose) Day the 4^(th) epcoritamab 30administration, 4- day consecutive corticosteroid administration iscontinued in Cycle 2 until epcoritamab dose is given without subsequentCRS event. *30 minutes to 2 hours prior to administration of epcoritamabNote: If epcoritamab dose is administered more than 24 h after the startof R-CHOP, the premedication is administered prior to epcoritamab doseand corticosteroid prophylaxis is continued for 3 days following theepcoritamab administration.

TABLE 5 Corticosteroid Dose Equivalents - Conversion TableGlucocorticoid Approximate equivalent dose (mg) Short-acting Cortisone(PO) 500 Hydrocortisone (IV or PO) 400 Intermediate-actingMethylprednisolone (IV or PO) 80 Prednisolone (PO) 100 Prednisone (IV orPO) 100 Triamcinolone (IV) 80 Long-acting Betamethasone (IV) 15Dexamethasone (IV or PO) 15

Supportive Care for Cytokine Release Syndrome

CRS is graded according to the ASTCT grading for CRS (Tables 6 and 7),and for treatment of CRS, subjects should receive supportive care.Supportive care can include, but is not limited to,

-   -   Infusion of saline    -   Systemic glucocorticosteroid, antihistamine, antipyrexia    -   Support for blood pressure (vasopressin, vasopressors)    -   Support for low-flow and high-flow oxygen and positive pressure        ventilation    -   Monoclonal antibody against IL-6R, e.g., IV administration of        tocilizumab    -   Monoclonal antibody against IL-6, e.g., IV siltuximab if not        responding to repeated tocilizumab.

Table 6: Grading and Management of Cytokine Release Syndrome

Harmonized definitions and grading criteria for CRS, per the AmericanSociety for Transplantation and Cellular Therapy (ASTCT), formerlyAmerican Society for Blood and Marrow Transplantation, (ASBMT), arepresented below.

Grading of Cytokine Release Syndrome

CRS parameter Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Fever¹ ≥38.0° C.≥38.0° C. ≥38.0° C. ≥38.0° C. With None Not requiring Requiring 1Requiring ≥2 Death due hypotension vasopressors vasopressor vasopressorsto CRS in with or (excluding which without vasopressin) anothervasopressin cause is not And/or None Requiring Requiring Requiring theprinciple hypoxia² low-flow high-flow positive factor (≤6 L/minute) (>6L/minute) pressure leading to nasal cannula nasal cannula, ventilation³this outcome or blow-by facemask, (eg, CPAP, nonrebreather BiPAP, mask,or intubation and venturi mask mechanical ventilation) Abbreviations:BiPAP, Bilevel positive airway pressure; CPAP, continuous positiveairway pressure; CRS, cytokine release syndrome; IV, intravenous. Note:organ toxicities or constitutional symptoms associated with CRS may begraded according to CTCAE but they do not influence CRS grading. ¹Feveris defined as temperature ≥ 38.0° C. not attributable to any othercause, with or without constitutional symptoms (eg, myalgia, arthralgia,malaise). In subjects who have CRS receiving antipyretics, anticytokinetherapy, and/or corticosteroids, fever is no longer required to gradesubsequent CRS severity. In this case, CRS grading is driven byhypotension and/or hypoxia. ²CRS grade is determined by the more severeevent: hypotension or hypoxia not attributable to any other cause. Forexample, a subject with temperature of 39.5° C., hypotension requiring 1vasopressor, and hypoxia requiring low-flow nasal cannula is classifiedas grade 3 CRS. Both systolic blood pressure and mean arterial pressureare acceptable for blood pressure measurement. No specific limits arerequired, but hypotension should be determined on a case-by-case basis,accounting for age and the subject's individual baseline, i.e., a bloodpressure that is below the normal expected for an individual in a givenenvironment. ³Intubation of a subject without hypoxia for the possibleneurologic compromise of a patent airway alone or for a procedure is notby definition grade 4 CRS. Source: Adapted from Lee et al., Biol BloodMarrow Transplant 2019; 25: 625-638

TABLE 7 Grading and Management of Cytokine Release Syndrome CRS gradeManagement 1 Fever: Patients with a new fever should be admitted to thehospital if not already. Investigate for infection and rapidly startupbroad-spectrum antibiotics. Continuation of antibiotic therapy isrecommended until and potential neutropenia resolve. Constitutionalsymptoms may be helped by NSAIDs. Tocilizumab: No*. Steroids: No. 2Fever: As per grade 1. Hypotension: Immediate clinical evaluation andintervention is warranted. At the first confirmed decrease ≥ 20% frombaseline systolic, diastolic or mean arterial pressure or evidence ofworsening perfusion, administer an IV fluid bolus (20 mL/kg up to 1 L).Consider a vasopressor and administer no later than after the 3^(rd) IVfluid bolus due the vasodilatation and capillary leak associated withCRS. Hypoxia: Consider X-ray or CT-scan if hypoxic and/or tachypneic.Administer oxygen by low-flow nasal cannula (≤6 L/min) or blow-by.Tocilizumab: No* (yes, if the patient has comorbidities^(†)). Steroids:No (consider, if the patient has comorbidities^(‡)). 3 Fever: As pergrade 1. Hypotension: Immediate clinical evaluation and intervention iswarranted. Administer a vasopressor (norepinephrine), with or withoutvasopressin, as most patients with CRS have peripheral vasodilation.Hypoxia: Administer oxygen by high-flow nasal cannula (>6 L/min),facemask, non- breather mask, or Venturi mask. Tocilizumab: Yes^(†).Steroids: Consider^(‡). 4 Fever: As per grade 1. Hypotension: Immediateclinical evaluation and intervention is warranted. Administer at least 2vasopressors, with or without vasopressin, as most patients with CRShave peripheral vasodilation. Hypoxia: Positive pressure (e.g. CPAP,BiPAP, intubation, and mechanical ventilation). Tocilizumab: Yes^(†).Steroids: Yes^(‡). *Consider intervening earlier in specific cases. Forexample, an elderly patient with prolonged fever (>72 hours) or veryhigh fever (>40.5° C./104.9° F.) may not tolerate the resulting sinustachycardia as well as a younger patient, so tocilizumab may beindicated. ^(†)Tocilizumab (anti-IL-6R) remains the only first-lineanticytokine therapy approved for CRS. If there is no improvement insymptoms within 6 hours, or if the patient starts to deteriorate afterinitial improvement, a second dose of tocilizumab should be administeredalong with a dose of corticosteroids. For patients being refractory totocilizumab (3 administrations), additional anticytokine therapy such assiltuximab (anti-IL-6) or anakinra (anti-IL-1R) may be considered.However, such use is entirely anecdotal and, as such, is entirely at thediscretion of the treating physician. ^(‡)Consider dexamethasone overmethylprednisolone due to improved CNS penetration even in absence ofneurotoxicity, as high-grade CRS is correlated with risk of concurrentor subsequent ICANS. If concurrent ICANS is observed, dexamethasoneshould be preferred. Source: (Varadarajan I, Kindwall-Keller T L, Lee DW (2020). Management of cytokine release syndrome. In: Chimeric antigenreceptor T-cell therapies for cancer (Chapter 5). Elsevier 2020)

Tumor Lysis Syndrome Prevention and Management

For prophylactic treatment of tumor lysis syndrome, subjects receivehydration and uric acid reducing agents prior to the administration ofepcoritamab. If signs of tumor lysis syndrome (TLS) occur, supportivetherapy, including rasburicase, is used.

Dose Modification Guidance and Safety Management

There will be no dose modification for epcoritamab (see FIG. 3 forexceptions in the dose escalation cohorts), although it may be held ordiscontinued depending on the nature of toxicities (and grade oftoxicities) subjects develop during their use.

Dose modifications for rituximab, cyclophosphamide, doxorubicin,vincristine, and prednisone should be done in accordance with therespective product labels in situations that differ from dosemodification recommendations provided below.

Treatment-emergent adverse events of R-CHOP combination therapypredominantly comprise hematologic toxicities (such as neutropenia,leucopenia, thrombocytopenia, and anemia). Nonhematologic disorders suchas asthenia, sensory disturbance, mucositis, alopecia, sepsis, dyspnea,back pain, hyperglycemia, hypersensitivity, and cardiac disorders haveall also been observed when treatment with R-CHOP has been administered.It is not always easy to assess the role of any 1 agent in these events;therefore, it is at the investigator's discretion to decide if 1 or moreagents are causal.

The start of a new cycle may be delayed on a weekly basis until recoveryof toxicity to a level allowing continuation of therapy. A subject whosecycle is delayed should be assessed weekly for resolution of toxicity.If toxicity persists after a 2-week cycle delay that is related to 1specific drug (vincristine, doxorubicin, etc.), the offending drugshould continue to be withheld and the new cycle should be started withthe remaining drugs. If R-CHOP chemotherapy is delayed, treatment withepcoritamab should be continued during the delay phase (provided thereason for delay is not toxicity potentially related to epcoritamabtherapy).

Subjects who discontinue any component of R-CHOP without diseaseprogression will continue epcoritamab for up to 16 cycles or until oneor more of the following discontinuation criteria are met: (a)unacceptable AE, (b) subject non-compliance, (c) pregnancy, (d) subjectrequest to discontinue treatment, (e) clinical progression, of (f)radiographic evidence of disease progression.

The following parameters must be met on the first day of each cycle(other than Cycle 1):

-   -   Platelet count >75×10⁹/L, or ≥50×10⁹/L if bone marrow        infiltration or splenomegaly (prior platelet transfusion is        allowed)    -   Hemoglobin ≥8 g/dL (≥4.96 mmol/L) (prior red blood cell        transfusion or recombinant human erythropoietin use is allowed)    -   ANC ≥1.0×10⁹/L (growth factor use is allowed)

Rituximab

Rituximab should be held for any Grade 4 toxicity or for anyrituximab-related, clinically significant, unmanageable Grade 3 adverseevent. Rituximab should be held until the adverse event returns tobaseline or resolves completely.

Cyclophosphamide

Dose adjustments for cyclophosphamide follow the local prescribinginformation. The most common adverse events experienced withcyclophosphamide are hematological toxicities; myelosuppression withleucopenia, anemia, and thrombocytopenia may occur. The lowest leukocyteand platelet levels occur in the first to second week after treatment isstarted. Recovery usually occurs within 3 to 4 weeks after treatment isstarted. Following treatment with cyclophosphamide, hemorrhagic cystitisand hematuria may occur. These may necessitate interruption of dosing.

The dose of cyclophosphamide should be adjusted on Day 1 of thesubsequent cycle of dosing when subjects develop hematologicaltoxicities thought to be causally related to cyclophosphamide.

TABLE 8 Dose Modification for Cyclophosphamide and Doxorubicin forHematological Toxicities ANC and Neutropenia Dose Given (any time duringcycle) Platelet count ^(a) (on next cycle) ≥1 × 10⁹/L >75 × 10⁹/L 100%of the designated dose >0.5 × 10⁹/L and no febrile >50 × 10⁹/L 100% ofthe designated dose neutropenia after recovery of ANC to 1.5 × 10⁹/L andplatelets to 100 × 10⁹/L <0.5 × 10⁹/L and/or febrile N/A Initiation ofG-CSF for all neutropenia (ANC < 0.5 × subsequent cycles is 10⁹/L +fever ≥ 38.5° C.) recommended <0.5 × 10⁹/L and/or febrile <50 × 10⁹/L25% dose reduction for neutropenia (ANC < 0.5 × subsequent cycles10⁹/L + fever ≥ 38.5° C. despite growth factors) Recurrence of <0.5 ×10⁹/L Recurrence of <50 × 10⁹/L Additional 25% dose and/or febrileneutropenia reduction for subsequent (ANC < 0.5 × 10⁹/L + cycles fever ≥38.5° C. despite growth factors) Third episode of <0.5 × 10⁹/L Thirdepisode of <50 × 10⁹/L Discontinue and/or febrile neutropenia (ANC < 0.5× 10⁹/L + fever ≥ 38.5° C. despite growth factors) Abbreviations: ANC =absolute neutrophil count; DLBCL = diffuse large B-cell lymphoma; G-CSF= granulocyte colony-stimulating factor. ^(a) Dose reductions due to lowplatelet counts or ANCs are not required in subjects withthrombocytopenia or neutropenia due to bone marrow infiltration fromDLBCL who entered the trial with platelet counts < 75 × 10⁹/L orneutrophil counts < 1.0 × 10⁹/L.

Doxorubicin

Dose adjustments for doxorubicin follow the provided prescribinginformation. The recommended lifetime cumulative dose limit ofdoxorubicin is 450 to 550 mg/m². The maximum dose given for each subjectis 300 to 400 mg/m², depending on the number of cycles given.Dose-limiting toxicities of doxorubicin therapy are mucositis,myelosuppression, and cardiotoxicity. Myelosuppression includesleucopenia, thrombocytopenia, and anemia, reaching nadir at 10 to 14days after treatment. The dose of doxorubicin should be adjusted on Day1 of the subsequent cycle of dosing when subjects develop hematologicaltoxicities thought to be causally related to doxorubicin (see Table 8above).

Cardiotoxicity as an arrhythmia can occur directly after administrationand ECG changes may last up to 2 weeks after administration.Cardiotoxicity may, however, occur several weeks or months afteradministration. Doxorubicin is metabolized by the liver and excreted inbile. Impairment of liver function results in slower excretion of thedrug and consequently increased retention and accumulation in the plasmaand tissues, resulting in enhanced clinical toxicity. Doxorubicin dosageis reduced if hepatic function is impaired, as shown in Table 9.

TABLE 9 Dose Modification of Doxorubicin for Hepatic Function ImpairmentSerum Bilirubin Levels* Recommended Dose 2.0-3.0 mg/dL 50% normaldose >3.0 mg/dL 25% normal dose *When bilirubin elevation isattributable to hepatotoxicity

Vincristine

Dose adjustments for vincristine must follow the provided prescribinginformation. The vincristine dosage is reduced if hepatic function isimpaired, as shown in Table 10.

TABLE 10 Dose Modification for Vincristine for Hepatic FunctionImpairment Serum Bilirubin Levels* Recommended Dose 2.0-3.0 mg/dL 75%normal dose >3.0 mg/dL 50% normal dose *When bilirubin elevation isattributable to hepatotoxicity

Vincristine doses is re-escalated when hyperbilirubinemia improves.These dose reductions are not required in subjects with Gilbert syndromeand in cases where the increase of bilirubin is due to non-hepaticreasons.

Neurologic toxicity is the most common adverse event experienced withvincristine and is related to dose and age. In case of severeneurotoxicity (Grade ≥3), vincristine should not be administered,especially if there are signs of paresthesia or paresis. For grade 3neuropathy, treatment may be resumed at 50% of the dose when symptomssubside. Vincristine is reduced by 25% for any episode ofileus/constipation requiring hospitalization. Vincristine is permanentlydiscontinued for Grade 4 neuropathy of any type.

Prednisone (or Equivalent)

Dose adjustments for prednisone (or equivalent) follow the providedprescribing information. Subjects administered high-dose prednisone orequivalent are monitored carefully as there is a relatively higher riskof developing or exacerbating some conditions (e.g., bacterialinfections, viral infections, systemic mycoses, hypertension, diabetesmellitus, and gastrointestinal conditions such as peptic ulcers,pancreatitis, and diverticulitis).

In the event that a subject develops an adverse event related tocorticosteroid and is not able to tolerate prednisone 100 mg (orequivalent), the dose is adjusted to a level specific to that subjectbut should be no less than prednisone 80 mg per day (so that the subjectstill receives a high dose of corticosteroid). In exceptionalcircumstances, a subject may not tolerate sudden steroid withdrawalafter 5 days of therapy. In such an instance, a tapering regimen of isindicated.

Study Assessments Demographics and Baseline Assessments

Demographic details of subjects are collected, as is information such asdate of lymphoma diagnosis, Ann Arbor Staging at diagnosis, includingconstitutional symptoms (B symptoms), and prior evidence of CD20positivity. Medical history, information regarding prior and concomitantmedications, concomitant procedures, and prior cancer therapies andsurgeries (including prior anti-cancer therapy for NHL, such as surgery,radiotherapy, chemo-radiotherapy, and systemic treatment regimens), arealso collected.

Efficacy Assessments

Eligible subjects have at least 1 measurable site of disease (asindicated in the inclusion criteria) for disease evaluations. Measurablesites of lymphoma are defined as lymph nodes, lymph node masses, orextranodal sites. Measurements are determined by imaging evaluation,with up to 6 measurable sites followed as target lesions for eachsubject. Sites not measurable as defined above are considered assessableby objective evidence of disease (i.e., radiographic imaging, physicalexamination, or other procedures). Examples of assessable diseaseinclude, e.g., bone marrow involvement, bone lesions, effusions, orthickening of bowel wall.

Tumor and Bone Marrow Biopsies

Two fresh core tumor biopsies are collected before treatment withepcoritamab (during the screening period) and 2 fresh core tumorbiopsies at the start of cycle 2 day 15 (±1 week) for all subjects withaccessible tumors. An archival tumor biopsy, if collected within 3months prior to enrollment, is acceptable if a fresh biopsy at screeningcannot be collected. The biopsy can be a whole lymph node or a corebiopsy. Tumor biopsies should be FFPE. Tumor biopsies are examined forMRD assessment and exploratory biomarkers.

Radiographic Assessments

An FDG PET-CT scan (or CT/MRI and FDG PET when PET-CT scan notavailable) is performed during Screening. For subjects with FDGavidtumors at Screening, all subsequent disease assessments include FDGPETusing the 5-point scale described in Barrington et al. (J Clin Oncol2014; 32:3048-58; Score 1: No uptake; Score 2: Uptake ≤mediastinum;Score 3: Update >mediastinum but ≤liver; Score 4: Uptake moderatelyhigher than liver; Score 5: Uptake markedly higher than liver and/or newlesions; Score X: new areas of update unlikely to be related tolymphoma). If contrast enhanced PETCT is not available, a standalonediagnostic CT/MRI and a standard FDGPET is performed. Subjects who areintolerant of IV CT contrast agents undergo CT scans with oral contrast.

MRI can be used to evaluate sites of disease that cannot be adequatelyimaged using CT or for subjects intolerant of CT contrast agents. Incases where MRI is the imaging modality of choice, the MRI is obtainedat screening and at all subsequent response evaluations.

Bone Marrow Assessments

A bone marrow biopsy (archival or fresh), with or without aspirate, isobtained at screening for all patients to document bone marrowinvolvement with lymphoma. A bone marrow biopsy obtained as routine SOCmay be used if taken up to 42 days before first dose of epcoritamab. Ifbone marrow aspirate is obtained, determination of bone marrowinvolvement can be confirmed by flow cytometry. A bone marrow biopsy istaken (1) at screening, (2) for subjects with bone marrow involvement atscreening who later achieve CR by imaging—bone marrow evaluationincludes morphological examination and either flow cytometry or IHC, ifwarranted, to confirm the presence or absence (complete remission) oflymphoma; (3) for subjects with bone marrow involvement documented atscreening who later achieve CR by imaging—a portion of the aspiratecollected to confirm CR will be used for MRD assessments.

Minimal Residual Disease Assessment

MRD is assessed by tracking the presence of DNA that encodes the B cellreceptor (BCR) expressed specifically by the cancer cells. The DNAsequence of this BCR is identified by tumor biopsy submitted atscreening. After the start of treatment, blood samples are taken atfixed timepoints and at the time of CR to assess whether the amount ofcancer DNA is declining, as a potential measure of (early) response, andto assess MRD. As an exploratory analysis, when a subject reaches ametabolic/radiologic CR and has bone marrow involvement documented atscreening, a portion of the aspirate collected to confirm CR is used toassess MRD.

Disease Response and Progressive Disease Assessment

Disease response is assessed according to both Lugano criteria(described in Cheson et al., J Clin Oncol 2014; 32:3059-68 (see, inparticular, Table 3 in Cheson et al., 2014) and LYRIC (Table 11) toinform decisions on continuation of treatment.

Endpoint definitions are as follows:

-   -   Overall response rate (ORR), is defined as the proportion of        subjects who achieve a response of PR or CR, prior to initiation        of subsequent therapy.    -   Time to response (TTR), is defined among responders, as the time        between first dose (from day 1, cycle 1) of epcoritamab and the        initial documentation of PR or CR.    -   Duration of response (DOR), is defined among responders, as the        time from the initial documentation of PR or CR to the date of        disease progression or death, whichever occurs earlier.    -   Progression-free survival (PFS), is defined as the time from the        first dosing date (day 1, cycle 1) of epcoritamab and the date        of disease progression or death, whichever occurs earlier.    -   Overall survival (OS), is defined as the time from the first        dosing date (day 1, cycle 1) of epcoritamab and the date of        death.    -   Time to next anti-lymphoma therapy (TTNT), is defined as the        number of days from day 1 of cycle 1 to the first documented        administration of subsequent anti-lymphoma therapy. MRD        negativity rate, is defined as the proportion of subjects with        at least 1 undetectable MRD result according to the specific        threshold, prior to initiation of subsequent therapy.        Lugano criteria (see, e.g., Cheson et al., J Clin Oncol 2014;        32:3059-68, for definitions of complete response, partial        response, no response/stable disease, and progressive disease)

(a) Target and Non-Target Lesions

Target lesions for the Lugano criteria include up to 6 of the largestdominant nodes, nodal masses, or other lymphomatous lesions that aremeasurable in two diameters and are preferably from different bodyregions representative of the subject's overall disease burden,including mediastinal and retroperitoneal disease, where applicable. Atbaseline, a measurable node is >15 mm in longest diameter (LDi).Measurable extranodal disease may be included in the six representativetarget lesions. At baseline, measurable extranodal lesions should be >10mm in LDi.

All other lesions (including nodal, extranodal, and assessable disease)may be followed as non-target lesions (e.g., cutaneous, GI, bone,spleen, liver, kidneys, pleural or pericardial effusions, ascites, bone,bone marrow).

(b) Split Lesions and Confluent Lesions

Lesions may split or may become confluent over time. In the case ofsplit lesions, the individual product of the perpendicular diameters(PPDs) of the nodes should be summed together to represent the PPD ofthe split lesion; this PPD is added to the sum of the PPDs of theremaining lesions to measure response. If subsequent growth of any orall of these discrete nodes occurs, the nadir of each individual node isused to determine progression. In the case of confluent lesions, the PPDof the confluent mass should be compared with the sum of the PPDs of theindividual nodes, with more than 50% increase in PPD of the confluentmass compared with the sum of individual nodes necessary to indicateprogressive disease (PD). The LDi and smallest diameter (SDi) are nolonger needed to determine progression.

LYRIC

Clinical studies have shown that cancer immunotherapies may result inearly apparent radiographic progression (including the appearance of newlesions), followed by a delayed response. As this initial increase intumor size might be caused by immune-cell infiltration in the setting ofa T-cell response, this progression may not be indicative of truedisease progression and is therefore called “pseudoprogression” (Wolchoket al., Clin Cancer Res 2009; 15:7412-20).

The current Lugano response assessment criteria (Cheson et al., J ClinOncol 2014; 32:3059-68) does not take pseudoprogression into account,and there is a significant risk of premature discontinuation of apotentially efficacious immunomodulatory drug following the observationof an atypical response. Atypical responses are characterized either bythe early progression of existing lesions, later followed by response,or by the development of new lesions, with or without tumor shrinkageelsewhere.

LYRIC is a modification of the Lugano response assessment criteria,which has been adapted to immune-based therapies, and it implements anew, mitigating response category: the “indeterminate response” (IR)designation (Cheson et al., Blood 2016; 128:2489-96). This IRdesignation was introduced to potentially identify “atypical response”cases until confirmed as flare/pseudoprogression or true PD by eitherbiopsy or subsequent imaging.

A subject who shows PD according Lugano criteria/classification will beconsidered to have IR in 1 or more of the 3 following circumstances:

-   -   IR (1): Increase in overall tumor burden (as assessed by sum of        the product of the diameters [SPD]) of ≥50% of up to 6 target        lesions in the first 12 weeks of therapy, without clinical        deterioration.    -   IR (2): Appearance of new lesions or growth of one or more        existing lesion(s) ≥50% at any time during treatment; occurring        in the context of lack of overall progression (SPD <50%        increase) of overall tumor burden, as measured by SPD of up to 6        lesions at any time during the treatment.    -   IR (3): Increase in FDG uptake of 1 or more lesion(s) without a        concomitant increase in lesion size or number.

It is possible that, at a single time point, a subject could fulfillcriteria for both IR(1) or IR(2) and IR(3): for example, there could bea new FDG-avid lesion in the absence of overall progression (IR[2]),and, at the same time, increase in FDG uptake of a separate lesion(IR[3]). In such cases, the designation of IR(1) or IR (2) should takepriority (e.g., IR[2] in the above example).

TABLE 11 LYRIC CR PR SD PD LYRIC Same as Same as Same as As with Luganowith the following Lugano Lugano Lugano exceptions: ClassificationClassification Classification IR Categories: IR (1): ≥50% increase inSPD in first 12 weeks of therapy IR (2): <50% increase in SPD with a)New lesion(s), or b) ≥50% increase of 1 lesion or set of lesions at anytime during treatment IR (3): Increase in FDG uptake without aconcomitant increase in lesion size meeting criteria for PD

Subjects categorized as having any of the IR types receive repeatimaging after an additional 12 weeks (or earlier if clinicallyindicated). At that time, response should be re-evaluated, and thesubject should be considered to have true PD with the followingconsiderations:

-   -   Follow-up IR(1): In case of IR(1), comparison should be made        between the first IR(1) and the current SPD. The IR(1) will        become PD if: (a) SPD increases by ≥10% from first IR1 AND (b)        an increase of ≥5 mm (in either dimension) of >1 lesion for        lesions ≤2 cm and ≥10 mm for lesions >2 cm, to be consistent        with Lugano criteria.    -   Follow-up IR(2): In case of IR(2), the new or growing lesion(s)        is added to the target lesion(s), up to a total of no more than        6 total lesions. The IR(2) will become PD if: (a) ≥50% increase        in SPD (newly defined set of target lesions) from nadir value.    -   Follow-up IR(3): The IR(3) will become PD if lesion with        increased FDG uptake also shows size increase.

Clinical Safety Assessments

Safety is assessed by measuring adverse events, laboratory test results,ECGs, vital sign measurements, physical examination findings, and ECOGperformance status. Also assessed are immune effector cell-associatedneurotoxicity syndrome (e.g., as described by Lee et al., Biol BloodMarrow Transplant 2019; 25:625-638), constitutional symptoms (Bsymptoms), tumor flare reaction, and survival.

Patient-Reported Outcomes

Patient-reported outcomes are evaluated using the FACT-Lymhealth-related quality of life (QOL) questionnaire, which assesses QOLin lymphoma patients.

Preliminary Results

As of 15 Jul. 2021, 9 patients have been treated with the combination ofepcoritamab+R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg) with 4patients completing ≥6 cycles. Median age was 66 years (range 56-78).All patients had stage III-IV disease. At data cutoff, all patientsremained on treatment with a median follow-up of 12.2 weeks (range2.2-28.2). The most common treatment-emergent adverse events werecytokine release syndrome (CRS) (56%, all grade 1/2), anemia (42%, allgrade 2/3), neutropenia (42%, all grade 3/4), fatigue (33%, all grade1/2), and peripheral neuropathy (33%, all grade 1/2). Notably, no grade≥3 CRS events or cases of febrile neutropenia were reported. Nodose-limiting toxicities had been observed. Four patients have had ≥1response assessment, with 3 achieving confirmed complete metabolicresponse (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and1 patient achieving confirmed partial metabolic response (epcoritamab 48mg cohort) by week 6; 2 of the 3 patients with CMR had responseassessments at 6 months, and both remained in CMR at that time. Bothdose cohorts have been cleared by the Dose Escalation Committee andSafety Committee, and the expansion part had been opened to enrolladditional patients.

As of Sep. 8, 2021, 24 patients had been dosed. The expansion phase 48mg was opened on Jun. 30, 2021. 7 responders were observed in doseescalation. The most common related AEs were CRS and Anemia. Majority ofCRS were Grade 1/2. There was one episode of Grade 3 CRS, which wastreated with tocilizumab and recovered. These data are preliminary andnon-validated and unclean data and response data were not completelyentered by site.

CONCLUSIONS

These preliminary data suggest that epcoritamab in combination withR-CHOP has a manageable safety profile with no new safety signals.Adverse events were similar to those previously reported for epcoritamabmonotherapy and R-CHOP. All evaluable patients achieved early responses,with all pts remaining on treatment. Updated and additional data frompatients treated in the expansion phase will be presented.

TABLE 12 Summary of Sequences SEQ ID Description Sequence 1huCD3 VH CDR1 GFTFNTYA 2 huCD3 VH CDR2 IRSKYNNYAT 3 huCD3 VH CDR3VRHGNFGNSYVSWFAY 4 huCD3 VL CDR1 TGAVTTSNY — huCD3 VL CDR2 GTN 5huCD3 VL CDR3 ALWYSNLWV 6 huCD3 VH1EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS 7 huCD3 VL1QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQADDESIYFCALWYS NLWVFGGGTKLTVL 8VH CD20-7D8 CDR1 GFTFHDYA 9 VH CD20-7D8 CDR2 ISWNSGTI 10VH CD20-7D8 CDR3 AKDIQYGNYYYGMDV 11 VL CD20-7D8 CDR1 QSVSSY —VL CD20-7D8 CDR2 DAS 12 VL CD20-7D8 CDR3 QQRSNWPIT 13 VH CD20-7D8EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLEWVSTISWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQGTTVTVSS 14 VL CD20-7D8EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITF GQGTRLEIK 15IgG1 heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSconstant region-WT GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK(amino acids positions RVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV118-447 according to VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVEU numbering). LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRECH3 region italics EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 16 IgG1-LFLEDA heavyASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS chain constant regionGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK (amino acids positionsRVEPKSCDKTHTCPPCPAPE FE GGPSVFLFPPKPKDTLMISRTPEVTCV 118-447 according toVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV EU numbering).LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 17 IgG1 F405LASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS (amino acids positionsGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK 118-447 according toRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV EU numbering)VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS F LLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 18 IgG1-K409RASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS (amino acids positionsGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK 118-447 according toRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV EU numbering)VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYS RLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 19 IgG1-LFLEDA-F405LASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS (FEAL)GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK (amino acids positionsRVEPKSCDKTHTCPPCPAPE FE GGPSVFLFPPKPKDTLMISRTPEVTCV 118-447 according toVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV EU numbering)LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS F LLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 20 IgG1-LFLEDA-K409RASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS (FEAR)GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK (amino acids positionsRVEPKSCDKTHTCPPCPAPE FE GGPSVFLFPPKPKDTLMISRTPEVTCV 118-447 according toVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV EU numbering)LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYS RLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 21 IgG1 CH3 regionGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG 22Constant region GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPhuman lambda LC VKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 23 Constant regionRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL human kappa LCQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC 24huCD3-LFLEDA-F405L EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLE (FEAL)WVARIRSKYNNYATYYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTA heavy chainMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF L LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 25 huCD3 VL + CL lightQAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAF chainRGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 26 CD20-7D8-LFLEDA-EVQLVESGGGLVQPDRSLRLSCAASGFTFHDYAMHWVRQAPGKGLE K409R (FEAR)WVSTISWNSGTIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAL heavy chainYYCAKDIQYGNYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA PE FEGGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS R LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 27 CD20-7D8 VL + CLEIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY light chainDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC 28Human CD3 (epsilon) MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDY EPIRKGQRDLYSGLNQRRI 29Human CD20 MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLGAVQIMNGLFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLVKGKMIMNSLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEKNSPSTQYCYSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKKEQTIEIKEEVVGLTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP Bold and underlinedare FE; A; L and R, corresponding to positions 234 and 235; 265; 405 and409, respectively, said positions being in accordance with EU-numbering.In variable regions, said CDR regions that were annotated in accordancewith IMGT definitions are underlined.

1. A method of treating diffuse large B-cell lymphoma (DLBCL) in a humansubject, the method comprising administering to the subject acombination of (a) epcoritamab or a biosimilar thereof (b) rituximab,(c) cyclophosphamide, (d) doxorubicin, (e) vincristine and (f)prednisone, in 21-day cycles, wherein (a) epcoritamab or a biosimilarthereof is administered subcutaneously, wherein (i) a priming dose isadministered on day 1 of the first 21-day cycle, an intermediate dose isadministered on day 8 of the first 21-day cycle, and a full dose of 24or 48 mg on day 15 of the first 21-day cycle, wherein the priming doseand intermediate dose are at a lower dose as compared with the fulldose, (ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second,third and fourth 21-day cycles; (iii) a full dose of 24 or 48 mg isadministered once every three weeks on day 1 of two to four subsequent21-day cycles; and (iv) a full dose of 24 or 48 mg is subsequentlyadministered one every four weeks on day 1 in 28-day cycles: (b)rituximab is administered intravenously at a dose of 375 mg/m² onceevery three weeks; (c) cyclophosphamide is administered intravenously ata dose of 750 mg/m² once every three weeks; (d) doxorubicin isadministered intravenously at a dose of 50 mg/m² once every three weeks;(e) vincristine is administered intravenously weeks at a dose of 1.4mg/m² once every three; and (f) prednisone is administered orally orintravenously at a dose of 100 mg once a day from day 1 to day 5 of each21 day cycle; wherein administration of the combination continues atleast until the subject exhibits a complete metabolic response (CMR), apartial metabolic response or stable disease, or until progressivedisease develops or unacceptable toxicity occurs.
 2. The method of claim1, wherein epcoritamab or a biosimilar thereof is administered at a fulldose of 24 mg.
 3. The method of claim 1, wherein epcoritamab or abiosimilar thereof is administered at a full dose of 48 mg. 4-11.(canceled)
 12. The method of claim 1, wherein the priming dose is 0.16mg. 13-14. (canceled)
 15. The method of claim 1, wherein theintermediate dose is 0.8 mg.
 16. (canceled)
 17. The method of claim 1,wherein the administration of rituximab once every three weeks isperformed for six or eight 21-day cycles. 18-19. (canceled)
 20. Themethod of claim 1, wherein the administration of cyclophosphamide onceevery three weeks is performed for six or eight 21-day cycles. 21-22.(canceled)
 23. The method of claim 1, wherein the administration ofdoxorubicin once every three weeks is performed for six or eight 21-daycycles. 24-25. (canceled)
 26. The method of claim 1, wherein theadministration of vincristine once every three weeks is performed forsix or eight 21-day cycles. 27-28. (canceled)
 29. The method of claim 1,wherein prednisone is administered for six or eight 21-day cycles.30-32. (canceled)
 33. The method of claim 1 wherein: (a) epcoritamab ora biosimilar thereof is administered as follows: (i) in cycle 1, apriming dose of 0.16 mg is administered on day 1, an intermediate doseof 0.8 mg is administered on day 8, and a dose of 24 mg is administeredon day 15; (ii) in cycles 2-4, a full dose of 24 mg is administered ondays 1, 8, and 15; (iii) in cycles 5 and 6, a full dose of 24 mg isadministered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, andvincristine are administered on day 1 in cycles 1-6; and (c) prednisoneis administered on days 1-5 in cycles 1-6.
 34. The method of claim 1,wherein: (a) epcoritamab or a biosimilar thereof is administered asfollows: (i) in cycle 1, a priming dose of 0.16 mg is administered onday 1, an intermediate dose of 0.8 mg is administered on day 8, and adose of 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, adose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide,doxorubicin, and vincristine are administered on day 1 in cycles 1-6;and (c) prednisone is administered on days 1-5 in cycles 1-6.
 35. Themethod of claim 33, wherein epcoritamab or a biosimilar thereof isadministered once every four weeks in 28-day cycles on day 1 from cycle7.
 36. The method of claim 1, wherein: (a) epcoritamab or a biosimilarthereof is administered as follows: (i) in cycle 1, a priming dose of0.16 mg is administered on day 1, an intermediate dose of 0.8 mg isadministered on day 8, and a dose of 24 mg is administered on day 15;(ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and15; (iii) in cycles 5-8, a dose of 24 mg is administered on day 1; (b)rituximab, cyclophosphamide, doxorubicin, and vincristine areadministered on day 1 in cycles 1-8; and (c) prednisone is administeredon days 1-5 in cycles 1-8.
 37. The method of claim 1 wherein: (a)epcoritamab or a biosimilar thereof is administered as follows: (i) incycle 1, a priming dose of 0.16 mg is administered on day 1, anintermediate dose of 0.8 mg is administered on day 8, and a dose of 48mg is administered on day 15; (ii) in cycles 2-4, a dose of 48 mg isadministered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 48 mgis administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin,and vincristine are administered on day 1 in cycles 1-8; and (c)prednisone is administered on days 1-5 in cycles 1-8.
 38. The method ofclaim 36, wherein epcoritamab or a biosimilar thereof is administeredonce every four weeks in 28-day cycles on day 1 from cycle
 9. 39-44.(canceled)
 45. The method of claim 1, wherein rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, and thebispecific antibody are administered sequentially.
 46. The method ofclaim 1, wherein prednisone is administered first, rituximab isadministered second, cyclophosphamide is administered third, doxorubicinis administered fourth, vincristine is administered fifth, andepcoritamab or a biosimilar thereof is administered last if rituximab,cyclophosphamide, doxorubicin, vincristine, prednisone, and thebispecific antibody are administered on the same day.
 47. The method ofclaim 1, wherein the DLBCL is double-hit or triple-hit DLBCL.
 48. Themethod of claim 1, wherein the DLBCL is follicular lymphoma Grade 3B.49. The method of claim 1, wherein the subject has an InternationalPrognostic Index (IPI) score or Revised-IPI score ≥3.
 50. The method ofclaim 1, wherein the subject has not received prior therapy for DLBCL orfollicular lymphoma Grade 3B. 51-63. (canceled)
 64. The method of claim1, wherein the method comprises administering a biosimilar ofepcoritamab comprising a heavy chain and a light chain consisting of theamino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavychain and a light chain consisting of the amino acid sequence of SEQ IDNOs: 26 and 27, respectively.
 65. The method of claim 1, wherein themethod comprises administration of epcoritamab.
 66. The method of claim34, wherein epcoritamab or a biosimilar thereof is administered onceevery four weeks in 28-day cycles on day 1 from cycle
 7. 67. The methodof claim 37, wherein epcoritamab or a biosimilar thereof is administeredonce every four weeks in 28-day cycles on day 1 from cycle 9.